Hybrid 2-aminotetralin and aryl-substituted piperazine compounds and their use in altering CNS activity

ABSTRACT

Hybrid compounds containing an aminotetralin moiety or a heterocyclic and/or open chain analog thereof linked through an alkylene group to an aryl ring system-substituted piperidiene moiety exhibit high levels of CNS activity, in some cases exhibiting especially high relative binding efficiencies between D3 and D2 dopaminergic receptor subtypes.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 11/235,612, filed Sep.26, 2005 (now U.S. Pat. No. 7,723,519, issued May 25, 2010), which is acontinuation-in-part of U.S. application Ser. No. 10/344,285, filed Feb.6, 2003 (now U.S. Pat. No. 6,982,332, issued Jan. 3, 2006), which is a371 U.S. national phase of International Application No. PCT/US02/18267,filed Jun. 7, 2002, now expired, which, in turn, claims the benefit ofU.S. provisional application Ser. No. 60/296,622, filed June 7, 2001,now expired. The entire disclosures of these patents and patentapplications are hereby incorporated by reference in their entireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to central nervous systempharmaceutically active compounds having both aryl-substitutedpiperazine and aminotetralin moieties, 5 or 7 membered cycloaliphaticring homologues thereof, or open chain analogues thereof; and to theirpharmacological use. These hybrid compounds exhibit high activity atvarious dopamine and serotonin receptor subtypes. Certain of thecompounds exhibit high differential selectivity between D2 and D3receptor subtypes.

2. Background Art

The dopamine receptors of the brain have proven fertile targets forpharmacological treatment of numerous central nervous system (“CNS”)disorders, including psychotic disorders such as schizophrenia andneurodegenerative disorders such as Parkinson's disease.⁸

In the last decade and a half, advances have been made in development ofdrugs specific for dopamine receptor subtypes, and in the development ofnovel pharmaceutically active compounds for their characterization.¹⁻³In addition, in 1990, a new dopamine subtype receptor now known as theD3 receptor was discovered and subsequently cloned from ratcomplimentary DNA libraries using probes derived from the D2 receptorsubtype.^(4,5) This new D3 receptor subtype belongs to the short form ofD2 receptor subtype, and bears close resemblance to the latter.^(5,6,7)

Therapies involving D2-specific drugs often are associated with sideeffects like EPS, Tardive dyskinesia, believed to originate fromblockage of D2 receptors in the striatal region of the brain.⁹ Studiesprobing the location of D3 receptors have shown that the distribution ofthe latter is different from the distribution of D2 receptors. In situhybridization studies showed a lack of adequate presence in the caudateputamen area of the striatal section, and a dominant presence in thenucleus accumbens area.¹⁰ These different distribution patterns renderthe D3 receptors unique targets for drug development. D3-specificantagonists and agonists are expected to have numerous applications intreatment of psychotic disorders and neurodegenerative diseases withoutthe undesirable side effects associated with pharmacology of the D2receptor.^(11,12,13) Recent studies have shown that D3 specificcompounds may also have therapeutic use in treatment of cocaine⁸addiction.^(14,15,16) Efforts have thus been made to develop D3 specificdrug candidates.

For example, 2-aminotetralins have been regarded as potent and selectiveagonists for D2 receptors.¹⁷⁻²⁰ However, 7-OH-DPAT and PD 128907, bothaminotetralins, have shown preferential activity at the D3 receptor.²¹Several other aminotetralin-related derivatives were also found to havesuch preferential selectivity.²² Aryl piperazines have also beendemonstrated to have activity toward the D2 and D3 receptors,^(23,24)and some of these were found to have both high affinity and selectivityfor the D3 receptor.²⁶ One such compound is GR103691,²⁵ containing aN-(methoxyphenyl)piperidine moiety linked to a 4′-acetyldiphenyl moietythrough an N-alkyl-N-urethane linking group. A series of8-hydroxy-2-aminotetralins bearing benzamide moieties have also beenshown to have selective affinity for the D3 receptor,^(27,28) and athiaza heterocyclic analog was shown to have high affinity andselectivity for this receptor subtype.²⁸

It would be desirable to provide additional pharmaceutically activecompounds which exhibit high levels of CNS activity, for example, withrespect to the dopaminergic receptors as well as the serotoninergicreceptors. It would be further desirable to provide drug candidateswhich exhibit high activity with respect to the D3 receptor subtype, andin particular to provide drug candidates which exhibit high selectivitybetween the D2 and D3 subtypes.

SUMMARY OF THE INVENTION

It has now been surprisingly discovered that hybrid compounds containingboth aminotetralin moieties, homologous 5 or 7 membered cycloaliphaticring moieties, or their heterocyclic and/or open chain analogues, inconjunction with an aryl-substituted piperazinyl moiety, exhibit highCNS activity, in particular high D3 affinity and/or D3/D2 selectivity.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The subject invention compounds are hybrid compounds containing both anaminotetralin moiety or related structure as hereafter defined, and anN′-aryl piperazinyl structure, linked to the “aminotetralin” structureby an alkylene bridge.

Each of the subject invention compounds thus contains a 1,4-piperidinylring structure, bonded at one nitrogen thereof to an organic groupcontaining an aryl group, including heteroaryl groups where theheteroatoms are N, O, S, or Se, and bonded at the other piperidinylnitrogen via an intervening alkylene group to nitrogen of anaminotetralin or analog thereof. The intervening alkylene group may bepart of a further ring structure containing the nitrogen of theaminotetralin. The aryl portion of the aminotetralin may constitute asubstituted or unsubstituted aryl ring such as a fused phenyl moiety, ormay be an analog, for example one containing a fused napthyl or higheraromatic moiety, or a 5 or 6 membered heteroaryl structure containing upto three heteroatoms individually selected from N, O, S, and Se.

Preferred embodiments include those of the general structure

wherein A is a C₆₋₁₀ aryl group, optionally substituted by an R² groupcomprising organyl groups preferably C₁₋₁₀ hydrocarbon groups optionallycontaining one or more O, N, S, or Se heteroatoms, more preferablyselected from among C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₄₋₈cycloalkyl, C₄₋₈ cycloalkenyl; C₆₋₁₀ aryl, —NR⁴ _(q) where R⁴individually are H or organyl groups, preferably H, C₁₋₈ alkyl, C₂₋₈alkenyl, C₄₋₈ cycloalkyl, C₄₋₈ cycloalkenyl, C₆₋₁₀ aryl and q is 2 or 3,with the proviso that when q is 3, the group bears a positive formalcharge; —NH—C(O)—R⁴, —NH—C(O)—NR⁴ ₂, and related compounds wherein thehydrocarbon groups in each case may optionally by substituted with —CN,C₁₋₄ lower alkyl, —OR⁴, —OH, halo, particularly fluoro and/or chloro,—CF₃, and the like. Two R² may also together form an alicyclic oraromatic fused five or six membered ring, optionally containingheteroatoms O, N, S, or Se, or containing a heteroaryl group substitutedonto or fused with the aryl ring. The heteroatoms of the heteroarylgroups may be individually selected from O, N, S, and Se. Examples ofpreferred A groups include, without limitation, the following:

where Z is a heteroatom or a CH or CH₂ group, at least one Z being aheteroatom. The aryl ring may contain no R² substituents, or aplurality, preferably not more than two R² substituents.

In the above general structure, B is an aminotetralin residue or analogthereof. For example, the aminotetralin residue may be the aminotetralinmoiety itself, optionally substituted, and linked via an alkylene bridgeto the piperidinyl nitrogen, such as:

wherein R¹ is an organo group, preferably selected from among C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₄₋₈ cycloalkyl, C₄₋₈ cycloalkenyl,C₆₋₁₀ aryl, each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl,etc. groups optionally halo substituted, preferably fluoro and/or chlorosubstituted, or substituted by —CN, C₁₋₄ lower alkoxy, C₁₋₄ acyloxy,C₁₋₄ acyl, —C(O)—R⁴, or —R⁵—NH—SO₂—NR⁴ _(r), and p is an integer,preferably 1 to 4, R¹ preferably being n-propyl and p preferably being2. However, the aminotetralin nitrogen may also be part of a ringstructure, optionally fused to the cycloaliphatic ring of theaminotetralin moiety, for example one of the structures

In the left most of these two structures, the (CH₂)_(p) alkylene linkinggroup is part of the ring structure per se. In each of these moieties,the tetralin moiety may have fused aryl or heteroaryl rings, or besubstituted by one or more R² substituents. Also, in the left-moststructure, the bond to the piperidinyl nitrogen is shown at the3-position relative to nitrogen, but can also be at the 1- or4-positions.

Examples of structures corresponding to the above-described embodimentsinclude the following:

wherein R¹ is an organo group, preferably selected from among C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₄₋₈ cycloalkyl, C₄₋₈ cycloalkenyl,C₆₋₁₀ aryl, each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl,etc. groups optionally halo substituted, preferably fluoro and/or chlorosubstituted, or substituted by —CN, C₁₋₄ lower alkoxy, C₁₋₄ acyloxy,C₁₋₄ acyl, —C(O)—R⁴, or —R⁵—NH—SO₂NR⁴ _(r) and p is an integer,preferably 1 to 4.

In one embodiment, the subject compounds have the following structure

is an aromatic and optionally heterocyclic ring system containing 5 or 6ring atoms and up to three heteroatoms individually selected from thegroup consisting of N, O, S, and Se, this aromatic ring systemoptionally substituted by o R² groups, where is 0, 1, 2, 3, or 4, theupper limit bounded by the number of available substituent sites. The R²groups are organyl groups preferably C₁₋₁₀ hydrocarbon groups optionallycontaining one or more O, N, S, or Se heteroatoms, more preferablyselected from among C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₄₋₈cycloalkyl, C₄₋₈ cycloalkenyl; C₆₋₁₀ aryl, —NR⁴ _(q) where R⁴individually are H or organyl groups, preferably H, C₁₋₈ alkyl, C₂₋₈alkenyl, C₄₋₈ cycloalkyl, C₄₋₈ cycloalkenyl, C₆₋₁₀ aryl and q is 2 or 3,with the proviso that when q is 3, the group bears a positive formalcharge; —NH—C(O)—R⁴, —NH—C(O)—NR⁴ ₂, and related compounds wherein thehydrocarbon groups in each case may optionally by substituted with —CN,C₁₋₄ lower alkyl, —OR⁴, —OH, halo, particularly fluoro and/or chloro,—CF₃, and the like. Two R² may also together form an alicyclic oraromatic fused five or six membered ring, optionally containingheteroatoms O, N, S, or Se.

R⁴ may also be arylsulfonyl, preferably 4-chlorophenylsulfonyl,3,4-dichlorophenylsulfonyl; 4-(trifluoromethyl)phenylsulfonyl; R⁶—Ar—SO₂where R⁶ is an electron withdrawing or electron donating substituent andAr is an aromatic or heteroaromatic moiety; or keto, preferablyphenylketo, 4-(trifluoromethyl)phenylketo, or aceto. Two R² may formpart of a fused cycloalkyl or aryl ring, optionally containing N, O, S,or Se heterocycles. For example, two R² may combine to form thestructures

R is H, C₁₋₄ lower alkyl, C₁₋₄ lower alkoxy, —CN, or is a methylenebonded to (CH)_(m), forming a 5 to 7 membered ring structure. In openchain analogues, m is 0 and R is not a methylene group bonded to(CH)_(m).

The compound contains n(CH)₂ groups, n being such that when m=0, n willbe 0, 1 or 2 and R will be a methylene group linking the aromatic 5 to 7membered ring with the CH group to form a cycloaliphatic ring structurewhich will contain 5 to 7 carbon atoms, or n is such that when thecompound is an open chain analog, n may range from 0 to 4. Thus, whenm=1 and n=1, the leftmost moiety in the formula will be an aminotetralinor heteroaryl analogue thereof.

R¹ is an organo group, preferably selected from among C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₄₋₈ cycloalkyl, C₄₋₈ cycloalkenyl, C₆₋₁₀ aryl,each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, etc. groupsoptionally halo substituted, preferably fluoro and/or chlorosubstituted, or substituted by —CN, C₁₋₄ lower alkoxy, C₁₋₄ acyloxy,C₁₋₄ acyl, —C(O)—R⁴, or —R⁵—NH—SO₂—NR⁴ _(r), where R⁵ is C₁₋₈ alkyleneand r is 2 or 3, with the proviso that when r is 3, the nitrogen of theNR⁴ _(r) group will bear a positive formal charge; —R⁵—NH—C(O)—R⁴;—R⁵—NR⁴ _(r), —R⁵—Ar where Ar is an aryl ring system, preferably a C₆₋₁₀aryl ring system, optionally including one or more heteroatoms,preferably phenyl, thienyl, pyridyl, biphenyl, or naphthyl.

The nitrogen of the aminotetralin or its heterocyclic and/or open chainanalog is bonded to a nitrogen of the piperazinyl group through theintermediacy of p(CH₂) groups, where p is 1 to 4, preferably 2 to 4.

A is an aryl group optionally containing one or more heteroatoms bondedto the remaining nitrogen of the piperazinyl group. The aryl group mayconsist of from 1 to 4 rings, optionally fused, and optionallysubstituted by C₁₋₄ alkyl, C₂₋₄ alkenyl, C₅₋₇ cycloalkyl, C₅₋₇cycloalkenyl, halo, preferably fluoro or chloro, C₁₋₄ aldehyde, —NR⁴_(q) and like groups. It should be noted that unsaturated groups such asalkenyl and cycloalkenyl include multiply unsaturated groups such asalkadienyl and cycloalkadienyl. Alkyl and cycloalkyl groups herein alsoinclude aryl-substituted alkyl and cycloalkyl groups, while aryl groupsalso include alkyl and cycloalkyl-substituted aryl groups. A ispreferably optionally substituted thienyl, pyridinyl, phenyl, biphenyl,or naphthyl, more preferably phenyl and biphenyl. All the substituentclasses of R, R¹, R², and R⁴ may be used as substituents on optionallysubstituted A. Preferred substituents include C₁₋₄ alkyl, —CN, halo,C₁₋₄ lower alkoxyl, and NH₂SO₂R⁴, CF₃, arylsulfonyl, arylsulfonamide,etc., more preferably o-OCH₃, 2,3-dichloro, and p-NHSO₂CH₃.

Preferred hybrid compounds include those having the structure I and IIbelow:

where I represents an aminotetralin or heterocyclic analog thereof,while II represents an open chain, optionally heterocyclic analogthereof, i.e. a compound similar in overall structure to I but where thesaturated aminotetralin ring is an open chain rather than cyclic moiety.In these and the foregoing formulae, X and Y are moieties which completea 5 or 6 membered aromatic ring system. For example, X together with Ymay be (CH)₄ forming a phenyl ring, or may be N—CH—S forming an thiazolering. It is preferably that the X,Y-containing ring be a phenyl,aminothiazolyl, or aminopyridyl ring system. Preferred “closed ring”aminotetralin moiety compounds thus include II, III, and IV below:

In addition, the saturated aminotetralin ring or its 5 to 7 memberedhomologue in such ring systems may also include O or S heteroatoms, i.e.structure V below:

Preferred open chain analogues have the structure VI:

Additional preferred open chain structures include

Typical dosages for mammalian species may vary from 0.001 mg/Kg of bodyweight to about 100 mg/Kg of body weight, preferably 0.01 mg/Kg to 5mg/Kg. The actual amount will vary depending upon the particular CNSactivity desired to be altered, and the desired degree of alteration.The upper limits may, as with virtually all drugs, be limited bytoxicity of the drug or its metabolites, or by the presence of unwantedside effects. The drugs may be administered in any form, but preferablyin the form of tablets or capsules with appropriate excipients. Dosages,forms of administration, etc., can be readily determined by thoseskilled in the art.

Guidelines to the effective dosages in mammalian species are provided bythe many known drugs commercially available which bind to CNS monoaminereceptor sites, and by comparing the binding affinities of thesepharmaceuticals with the target compounds of the subject invention by invivo and in vitro studies. In addition to the utility of the subjectinvention compounds in treatment of diseases such as Parkinson'sdisease, schizophrenia, treatment for addiction such as cocaineaddiction, and the like, the subject invention compounds are alsouseful, particularly in their radio labeled form, for clinical studiesdirected to distribution of monoamine receptor sites in the brain andthe effect which compounds such as cocaine have on these sites.

All the compounds described above can be synthesized by techniques wellknown to those skilled in organic synthesis. Among the compoundssynthesized are those included in Tables 1, 2, and 3 below. Table 1includes aminotetralin hybrids per se, while Table 2 includesheterocyclic analogs thereof. In both Table 1 and Table 3, the leftmostaromatic ring is a phenyl ring, i.e., as shown in structures II and VI,respectively. Table 3 includes “open chain” analogues. In the tables,the substituent headings are those the corresponding to structuralformulae II (Table 1); I (Table 2); and VI (Table 3). In Table 2, the“Ring” column specifies the heterocyclic ring portion which includes Xand Y of structure I. The compounds identified in the tables representcompounds tested for CNS activity, the results of which are presented inTables 4-8. However, additional compounds have been synthesized as well,as reported herein.

The compounds may be used per se or as pharmaceutically acceptablederivatives. The latter term includes salts, esters, and otherderivatives generally considered acceptable by pharmaceutical standards.Useful derivatives, for example, include salts of organic and inorganicacids such as sulfates, phosphates, hydrohalide salts, carboxylatesalts, etc., as well as esters of carboxylic acid or hydroxylsubstituents, ethers of hydroxyl substituents, amides of aminosubstituents, as well as carbamates, ureas, etc. Synthesis of thesederivatives is conventional, and well known to those skilled inpharmaceutical chemistry. For example, compounds bearing hydroxyl groupsmay be converted to esters by customary techniques of organic chemistry,such as reaction with an acyl halide, carboxylic acid anhydride, or byesterification with an acid while removing byproduct water. In somecases, derivation may be desired to facilitate compounding of thepharmaceutical into an acceptable form such as tablets, powder, aqueousdispersion, capsule, etc., or may be useful in assisting bioavailabilityof the drug following administration, for example by rendering thecompound more or less soluble. In many cases, such as, for example,esters, ureas, carbamates, ethers, etc., the derivative may act as“prodrug,” which liberates the active form by biological transformation,i.e., by enzymatic hydrolysis of an ester functionality, as is wellknown to the pharmaceutical chemist.

TABLE 1 Compound R² R¹ p A  8 7-OH 3-cyanopropyl 4 phenyl 10a 7-OH(4-benzoylamino)butyl 4 phenyl 10b 7-OH (2-benzoylamino)ethyl 4 phenyl12a 7-OH propargyl 2 phenyl 12b 7-OH propargyl 4 phenyl 15a 7-OH propyl2 phenyl 15b 7-OH propyl 4 phenyl 19a 7-OH propyl 4 2,3- dichlorophenyl19b 7-OH propargyl 4 2,3- dichlorophenyl

TABLE 2 Compound* Ring R² R¹ A 23

2-NH₂ propyl phenyl 25

2-NH₂ propyl phenyl *p is 2 in each of the compounds of Table 2.

TABLE 3 Compound R² R¹ n* p A 29a 4-NH₂ propyl 1 2 phenyl 29b 3-NH₂propyl 1 2 phenyl 30a 4-NHSO₂-φ-4Cl propyl 1 2 phenyl 30b 3-NHSO₂-φ-4Clpropyl 1 2 phenyl *m = 0 in all the open-chain compounds in Table 3.

CNS activity was assessed by in vitro testing on cloned human dopamineand serotonin receptors by standard techniques. These techniques areknown by those skilled in the art to reflect in vivo activity.Techniques and their relationship to CNS activity are well known.²⁹⁻³⁵

Initial efforts resulted in the design and synthesis of novel compounds12b and 15b. In designing of 10a-b it was decided to incorporate anadditional benzamide moiety into the structural base to enhance thebinding of these novel analogs by accessing the accessible domains inthe receptor. It was conceived that such moieties might play a role inselectivity as well as activity.

These compounds were characterized for their binding at the cloneddopamine D₁, D₂, D₃ and D₄ receptor subtypes and also at the 5HT_(1A),5HT_(2A) and 5HT_(2C) serotonin receptors subtypes (Tables 4 to 8).Compounds 15b and 12b with a 4-methylene long linker exhibited markedpotency for the both D2 and D3 receptors and much weaker activity forthe D1 receptor (Table 4). In addition, compounds 12b and 15b showedgood affinity at the D4 receptor and were full agonists at thisreceptor. In the functional assay, compounds 15b and 12b showedpreferential agonist activity at the D3 receptor while showing partialagonism at the D3 receptor (Table 7). On the other hand, compound 15awith a shorter, two-methylene chain linker, was more selective at the D3receptor (Tables 1 and 5). The selectivity of 15a in this regard wasmore than two fold than the standard 7-OH-DPAT when assessed by theprotocol used in Table 4 and was one of the most selective compounds inthis series. The replacement of the phenyl group in 15b by a2,3-dichlorophenyl moiety resulted in 19a which showed improvedselectivity for the D3 receptor (15 vs.1) compared to 15b. Replacementof the phenol moiety in compound 15a by a thiazolidinium moiety in 25also resulted in much greater selectivity for the D3 receptor (Table 4;Table 8).

Amide-substituted piperazine derivatives 10a-b, were less active eitherat the dopamine or at the serotonin receptor subtypes while the cyanocompound 8 showed modest activity at these receptors (Table 1 and 3).

Various compounds were tested against serotonin receptor subtypes. Asshown in Table 6 these compounds were weak in their binding to theserotonin receptor subtypes except compounds 15a-b and 12a-b whichshowed good potency at the 5HT1A receptor.

Open chain analog compounds 30a-b were also synthesized and biologicallycharacterized. SAR results indicate that compounds 30a-b with anelectron withdrawing substituent are more potent than compounds notcontaining such a substituent (Table 5).

Biological Methods:

Biological studies were carried out with cloned human dopamine andserotonin receptors as described below.

D1 Receptor

LHD1 cells (human receptor) are grown and prepared as described for theHA7 cells as described hereafter. The final pellet is resuspended at 5mg protein/80 ml in 50 mM Tris-HCl containing 120 mM of NaCl, 5 mM ofKCl, 2 mM of CaCl₂, and 1 mM of MgCl₂, pH 7.4. To wells containing 100μl of test drug or buffer and 100 ml of [³H]SCH 23390 (0.18 nM finalconc.), is added 0.8 ml of cell homogenate (0.05 mg protein/well), andthe plates are incubated at 250° C. for 60 min. Nonspecific binding isdetermined with 1 μM of SCH 23390.

D2 and D3 Receptors

CHOp-cells (human receptors) are grown to confluence in a minimumessential medium (α MEM) containing 10% fetal calf serum, 0.05%pen-strep, and 600 μg/ml of G418. The cells are scraped from the 100 by20 mm plates and centrifuged at 500. g for 5 min. The pellet ishomogenized by polytron in 50 mM Tris-HCl, pH 7.7, and centrifuged at27,000·G for 12 min. The pellet is resuspended in 50 mM Tris, D₂ at 5 mgprotein/ml, D₃ at 1 mg protein/ml, and stored at −70° C. in 1-mlaliquots.

On the day of the experiment, CHOp-D₂ or CHOp-D₃ cells are thawed,resuspended in 50 mM Tris, and centrifuged at 27,000·G for 12 min. Thepellet is then resuspended at 5 mg protein/80 ml (D₂) and 1 mgprotein/80 ml (D₃) in 50 mM Tris containing 120 mM of NaCl, 5 mM of KCl,1.5 mM of CaCl₂, 4 mM of MgCl₂, and 1 mM of EDTA, pH 7.4. Then 0.8 ml ofcell homogenate (0.05 and 0.01 mg protein/well, D₂ and D₃ respectively)is added to wells containing 100 μl of the test drug or buffer and 100μl of [³H]YM-09151-2 (0.21 nM final conc.). Nonspecific binding isdetermined with 1 mM of chlorpromazine. The plates are incubated at 25°C. for 60 min before filtration and counted as usual. The filters aresoaked in 0.1% PEI before filtering.

D4 Receptor

CHO D4.4 cells (human receptors) are grown to confluence in D₄ Puromycinmedium containing 2 μg/ml puromycin, 5% fetal calf serum and 5supplemented calf serum and 0.5% pen-strep. The cells are harvested asdescribed for D₂ and D₃ cells and used at a concentration of 0.15 mgprotein/well in the [³H]YM-09151-2 binding assay.

5-HT1A Receptor

HA7 cells (human receptor) are grown to confluence in DMEM containing10% fetal calf serum, 0.05% penicillin-streptomycin (pen-strep), and 400mg/ml of G418. The cells are scraped from the 100 by 20 mm plates andcentrifuged at 500·G for 5 min. The pellet is homogenized in 50 mMTris-HCl, pH 7.7, with a polytron, centrifuged at 27,000·G andresuspended at 10 mg protein/ml in the same buffer. The homogenate isthen stored at −70° C. in 1-ml aliquots.

The thawed cells are washed once and resuspended at 10 mg protein/80 mlin 25 mM Tris-HCl containing 100 μM of ascorbic acid and 10 mM ofnialamide at pH 7.4. The assay is performed in triplicate in a 96-wellplate. To 100 μl of [³H]8-OH-DPAT (0.5 nM final conc), 100 ml of testcompound or buffer and 0.8 ml of cell homogenate (0.1 mg protein/well)is added to each well by a Tomtec Quadra 96. Nonspecific binding isdefined using 1 μM dihydroergotamine. The plates are incubated at 25° C.for 60 min, then filtered. The incubation is terminated by rapidfiltration through glass fiber filter paper on a Tomtec cell harvester.The filters are washed four times with ice-cold 50 mM Tris-HCl, pH 7.7,dried overnight, bagged with 10 ml scintillation cocktail beforecounting for 2 min. on a Wallac Betaplate 1205 liquid scintillationcounter.

Results of testing of several representative compounds for bindingaffinity at the D1, D2, D3 and D4 dopaminergenic receptor subtypes arepresented in Table 4, along with 7-OH DPAT, known to have high affinityfor the D3 receptor subtype and relatively high differential affinitybetween the D3 and D2 receptor subtypes. In interpreting the table, itshould be noted that low values represent high affinity, i.e. highdisplacement of the reference binding ligand. Higher D2/D3 ratios thusrepresent higher relative affinity for the D3 receptor subtype ascompared with the D2 receptor subtype. Preferred compounds have at least1.5 times the D2/D3 ratio of 7-OH DPAT when measured by the sameprotocol.

TABLE 4 Binding Affinity at the Cloned Human D1, D2, D3 and D4 ReceptorsKi(nM), D1 Ki(nM), D2 Ki(nM), D3 Compound [³H]SCH23390 [³H]YM-09151-2[³H]YM-09151-2 Ki(nM), D4 D2/D3 7-OH-DPAT  2548 ± 1082  16 ± 2.0 1.5 ±0.4 10.6  8 3217.7 ± 7.77  89.79 ± 32.53 75.78 ± 6.29  142.26 ± 6.50 1.18 10a 3734.7 ± 272   119.16 ± 1.45  313.19 ± 6.47  136.9 ± 10.19 0.3810b 2947.86 ± 237.81 110.94 ± 32.19  84.62 ± 1.55  35.63 ± 1.42  1.3012a 662.6 65.5 23.48 2.8 12b 676.77 ± 34   6.54 ± 1.14 6.58 ± 1.15 28.93± 4.41  1 15a >10000 75.48 3.2 25 15b 6119.68 ± 932.83 3.37 ± 0.78 3.47± 0.08 25.66 ± 25.66 1 19a 4062.6 31.53 2.66 15 19b 1718.28 28.09 12.692.3

Table 4 indicates that all of the compounds tested had relatively highaffinity for the D2, D3, and D4 receptor subtypes. Most had littleaffinity for the D1 receptor. Thus, all these compounds would beexpected to exhibit CNS activity in vivo. Particularly noteworthy arecompounds 15a and 19a, which exhibit considerably lower D1 receptoractivity relative to 7-OH DPAT, and even higher activity differential asbetween the D2 and D3 receptors.

Various open chain analogues, those identified in Table 3, were alsotested with respect to their binding affinities at the D2 and D3receptors, as compared to 7-OH DPAT. The results are presented in Table5.

TABLE 5 Binding Affinity at the Cloned Human D2 and D3 Receptors Ki(nM),D2 Ki(nM), D3 Compound [³H]Spiperone [³H]Spiperone (+)-7-OH-DPAT  538 ±108 5.00 ± 1.18 29a 25,553 ± 2,898 1,152 ± 130   29b 23,517 ± 2,0971,478 ± 247   30a 702 ± 22 5.98 ± 0.70 30b 552 ± 31 36.8 ± 5.4 

Noteworthy is the exceptionally low affinity of compounds 29a and 29bfor the D2 receptor, while showing some activity at the D3 receptor, andcompound 30a, which exhibits differential binding affinity between theD2 and D3 receptors which is higher than that of 7-OH DPAT.

The compounds tested against dopaminergenic receptors and reported inTable 4 were also tested for binding affinity to the cloned human 5HT1A,5HT2A, and 5HT2C serotonin receptors. A wide range of binding activityand differential binding activities considerably different from theactivity exhibited by 7-OH DPAT is evident from the results presented inTable 6.

TABLE 6 Binding Affinity at the Cloned Human 5HT1A, 5HT2A and 5HT2CReceptors Ki (nM), 5HT1A Ki (nM), 5HT2A Ki (nM), 5HT2C Compound[³H]8-OH-DPAT [³H]Ketanserin [³H]Mesulergine 7-OH-DPAT  193 ±3.4 >10,000 >10,000  8 88.31 ± 0.40 700.77 ± 16.78 >10,000 10a 171.48 ±32.17 1231.23 ± 217   >10,000 10b 163.98 ± 27.48 287.44 ± 50.24 >10,00012a 27.64 160.6 2693.4 12b 15.25 ± 3.34 260.23 ± 41.94 3222.88 ± 52.9015a 21.42 1541.59 >10,000 15b 18.47 ± 2.46 1784.26 ± 614.31 >10,000 19a40.56 355.79 638.54 19b 64.38 160.22 264.28

Potential as domaminergenic agonists was assayed by ³H-thymidineincorporation by standard techniques. The results are presented in Table7.

TABLE 7 Evaluation of Agonist Potency by [³H]Thymidine IncorporationExperiment D2 % Maxm D3 % Maxm D4 % Maxm Compound EC50 (nM) Stim EC50(nM) Stim EC50 (nM) Stim 7-OH-DPAT 4.2 ± 2.2 0.9 ± 0.6  8 74.49 ± 32.9154.09 ± 4.82 68.11 ± 36.70 67.07 ± 1.93  54.76 ± 18.60 10a 115.28 ±20.22  44.91 ± 0.84 110.23 ± 33.27  44.06 ± 11.55 32.21 ± 2.51  51.08 ±1.72  10b 97.16 ± 47.74 27.03 ± 5.54 104.33 ± 57.28  50.93 ± 12.63 26.74± 10.55 71.36 ± 10.17 12a 6.18 ± 0.18 87.20 ± 2.16 1.25 ± 0.08 94.53 ±6.17  12b 3.55 ± 1.34 85.01 ± 6.26 0.25 ± 0.03 71.69 ± 10.56 23.92 ±3.57  85.15 ± 17.64 15a 1.59 ± 0.06 104.66 ± 11.33 0.97 ± 0.02 84.62 ±10.75 15b 3.21 ± 0.46 120.72 ± 26.15 0.91 ± 0.46 74.92 ± 9.05  22.53 ±10.98 102.81 ± 20.21  19a 8.31 ± 0.69 80.09 ± 8.15 6.49 ± 2.46 85.67 ±1.19  19b 11.81 ± 1.84  85.66 ± 9.15 3.08 ± 1.09 90.34 ± 15.50

The mitogenesis study results presented in Table 7 assay the ability ofthese ligands to act as agonists or antagonists. The EC50 values thusindicate intrinsic activities or functional activities of thesecompounds. The value of % maximum stimulation indicates whether acompound is a partial agonist or full agonist. Generally, a valuegreater than 80% is considered as a full agonist and anything less than80% is considered as a partial agonist. A compound will be consideredantagonist if it produces a negative result (no [3H]thymidineincorporation) in the assay. All the compounds reported in Table 7 areeither full agonists or partial agonists.

Inhibition constants for binding to cloned D2L and D3 receptorsexpressed in HEK cells by displacing [³H] spiperone were measured forseveral compounds. The results are presented in Table 8 below.

TABLE 8 Inhibition Constants for Binding to the Closed D2L and D3Receptors Expressed in HEK Cells by Displacing [³H]spiperone D2L HEKCells D3 HEK Cells [³H]spiperone [³H]spiperone Compound Ki (nM) Ki (nM)D2L/D3 (+)-7-OH-DPAT  538 ± 108 5.00 ± 1.18 107.6  8  622 ± 102 50.2 ±7.1  12.4 10a 782 ± 42 756 ± 48  1 10b 354 ± 2  55.7 ± 5.5  6.3 12a 245± 26 14.2 ± 1.7  17.2 12b 68.4 ± 7.6 1.40 ± 0.14 48.9 15a 213 ± 26 1.75± 0.34 121.7 15b 114 ± 8  3.79 ± 0.40 30 19a  8.78 ± 0.81 2.26 ± 0.503.8 19b  7.37 ± 0.27 3.59 ± 0.58 2.0 19c 27.4 ± 1.0 1.13 ± 0.04 24.2 231120 ± 144 22.3 ± 2.3  50 25 2080 ± 162 4.14 ± 0.55 502Synthetic Procedures

A general synthetic scheme may be described as follows. Phenylpiperazineon N-alkylation with N-(4-bromoalkyl)phthalimide in presence of a basefurnished 3a-b which on reaction with hydrazine released amine 4a-b.Reductive amination reaction of amine 4a-b with 7-methoxytetralone understandard conditions furnished amine 5a-b in good yield. N-Alkylationwith bromocyanide resulted in cyano compounds 6a-b which were convertedinto amines 7a-b by reaction with lithium aluminum hydride (LAH).Demethylation of 6a with BBr₃ produced compound 8. Conversion of amines7a-b to benzamide derivatives followed by demethylation producedcompounds 10a-b. Similarly alkylation of 5a-b with propyl bromideproduced N-alkylated derivatives which on demethylation produced finaltarget compounds 12a-b. N-Acetylation of 5a-b followed by reduction withLAH furnished 14a-b. Demethylation of 14a-b produced final 15a-b. Thedichloro compounds were synthesized in a similar manner.

Amine 4a was reacted with two isomeric nitrophenylacetic acidderivatives respectively to produce 26a-b which were converted to 28a-bby first reduction with BH₃ generated in situ by reaction of BF₃ withNaBH₄, followed by reaction with propionyl chloride to produce theintermediate amides. Final amine targets 29a-b were produced byreduction of the nitro group in compounds by catalytic hydrogenationfollowed by borane reduction The compounds 29a-b were converted intotargets 30a-b by reacting with 4-chloro-phenylsulfonyl chloride. Amine4a was reacted with 4-fluoropheneacetyl chloride to produce amide 26which on reduction with lithium aluminum hydride followed byN-propylation produced the target 27. These reaction are presented ingreater detail below.

Procedure A

N-[2-(4-Phenylpiperazin-1-yl)-ethyl]-phthalimide 3a

A mixture of 1-phenylpiperazine 2 (2.59 g, 15.98 mmol) was reacted withN-(2-bromoethyl)phthalimide (8.12 g, 31.96 mmol), Et₃N (2.0 mL) andK₂CO₃ (8.0 g) in DMF (40 mL) and stirred at 70° C. under N₂ overnight.After the reaction mixture was cooled down, water (100 mL) was added.The mixture was extracted with diethyl ether. The organic phase wascombined and dried over Na₂SO₄. The solvent was removed under vacuo togive the crude product, which was purified by flash chromatography(Hexane/EtOac=1/1) to furnish 3a, 3.81 g (71%) ¹HNMR (CDCl₃) 2.68-2.72(m, 6H, N(CH₂)₂, CONCH₂), 3.12-3.15 (t, J=4.8 Hz, 4H, N(CH₂)₂),3.84-3.89 (t, J=6.3 Hz, 2H), 6.80-6.82 (t, J=8.1 Hz, 1H, Ar—H),6.88-6.91 (d, J=8.1 Hz, 2H, Ar—H), 7.21-7.26 (t, J=8.1 Hz, 2H, Ar—H),7.69-7.86 (m, 4H, Ar—H).

N-[4-(4-Phenylpiperazin-1-yl)-butyl]-phthalimide 3b

1-Phenylpiperazine 2 (2.21 g, 7.81 mmol) was reacted withN-(4-bromobutyl)phthalimide (1.26 g, 7.81 mmol) in the presence of K₂CO₃(8.0 g) in Et₃N (1.0 mL) and DMF (20 mL) to give a yellow solid 3a, 2.70(95%) (Procedure A). ¹H NMR (CDCl₃) 1.55-1.82 (m, 4H, CH₂CH₂), 2.40-2.45(t, J=7.5 Hz, 2H, NCH₂), 2.57-2.61 (t, J=4.8 HZ, 4H, N(CH₂)₂), 3.17-3.20(t, J=4.8 Hz, 4H, N(CH₂)₂), 3.71-3.75 (t, J=6.7 Hz, 2H, NCH₂), 6.82-6.94(3H, Ar—H), 7.23-7.28 (m, 2H, Ar—H), 7.70-7.74 (m, 2H, Ar—H), 7.83-7.86(m, 2H, Ar—H).

Procedure B

2-(4-Phenylpiperazin-1-yl)-ethylamine 4a

Into the solution of compound 3a (1.97 g, 5.88 mmol) in EtOH (25 mL) wasadded NH₂NH₂ (1.0 g, 31.2 mmol). The reaction mixture was stirred atroom temperature under N₂ for 24 h. The solvent was removed under vacuo.EtOAc was added. The mixture was filtered and the solution was collectedand dried over Na₂SO₄. The solvent was removed under vacuo to give awhite solid 15, 1.18 g (98%) ¹NNMR (CDCl₃) 2.46-2.51 (t, J=6.3 Hz, 2H,CH ₂NH₂), 2.68-2.71 (t, J=4.8 Hz, 4H, N(CH₂)₂), 2.86-2.92 (t, J=6.3 Hz,2H, NCH₂), 3.12-3.16 (t, J=4.8 Hz, 4H, N(CH₂)₂), 6.81-6.83 (t, J=8.1 Hz,1H, Ar—H), 6.88-6.91 (d, J=8.1 Hz, 2H, Ar—H), 7.21-7.26 (t, J=8.1 Hz,2H, Ar—H).

4-(4-Phenylpiperazin-1-yl)-butylamine 4b

Compound 3b (7.70 g, 21.21 mmol) was reacted with NH₂NH₂ (3.0 g, 93.75mmol) in EtOH (60 mL) to give 4b, 4.60 g (93%) (Procedure B). ¹H NMR(CDCl₃) 1.48-1.61 (m, 4H), 2.83-2.43 (t, J=7.2 Hz, 2H, NCH₂), 2.61-2.63(t, J=4.5 Hz, 4H, N(CH₂)₂), 2.72-2.76 (t, J=6.4 Hz, 2H, NCH₂), 3.19-3.22(t, J=4.6 Hz, 4H, N(CH₂)₂), 6.33-6.94 (m, 3H, Ar—H), 7.23-7.28 (m, 2H,Ar—H).

Procedure C

7-Methoxyl-2-[(N-(4-phenylpiperazin-1-yl)ethyl)-amino]tetralin 5a

A mixture of compound 4a (1.18 g, 5.75 mmol), 7-methoxyl-tetralone (1.22g, 6.93 mmol) and Na(OAc)₃BH (3.60 g, 17.26 mmol) in ClCH₂CH₂Cl (20 mL)and HOAc (1.0 mL) was stirred at room temperature under N₂ overnight.After the solvent was evaporated, saturated NaHCO₃/H₂O (10 mL) was addedand the mixture was extracted with EtOAc. The combined organic phase wasdried over Na₂SO₄ and evaporated to give the crude product, which waspurified by flash chromatography (EtOA/MeOH/Et₃N=50/5/1) to give solid5a, 1.95 g (93%). ¹HNMR (CDCl₃) 1.60-1.68 (m, 2H), 2.60-2.63 (m, 6H,CH₂N(CH ₂)₂), 2.76-3.04 (m, 7H), 3.16-3.20 (t, J=4.8 Hz, N(CH₂)₂), 3.77(s, 3H, CH₃O), 6.62-6.71 (m, 2H, Ar—H), 6.64-7.02 (m, 4H, Ar—H),7.24-7.30 (m, 2H, Ar—H).

7-Methoxyl-2-[(N-(4-phenylpiperazin-1-yl)-butyl)amino]tetralin 5b

4-(4-Aminobutyl)-1-phenylpiperazine 4 (4.30 g, 18.30 mmol) was reactedwith 7-methoxyl -2-tetralone (3.21 g, 18.24 mmol) and Na(OAc)₃BH (11.40g, 54.03 mmol) in 1,2-dichloroethane (50 mL) and HOAc (1.0 mL) to give asolid 5b 5.80 g (81%) (Procedure C). ¹H NMR (CDCl₃) 1.58-1.60 (m, 4H),2.03-2.07 (m, 2H), 2.40-2.47 (t, J=6.7 Hz, 2H), 2.59-2.60 (t, J=4.8 Hz,m, 4H, N(CH₂)₂), 2.68-2.85 (m, 5H), 2.91-3.03 (m, 2H), 3.19-3.22 (t,J=4.8 Hz, 4H, N(CH₂)₂), 3.76 (s, 3H, CH₃O), 6.61-6.67 (m, 2H, Ar—H),6.82-6.97 (m, 4H, Ar—H), 7.23-7.29 (m, 2H, Ar—H). Anal. C₂₅H₃₅N₃O Calcd:C, 76.29; H, 8.95; N, 10.68. Found: C, 76.08; H, 9.00; N, 10.57.

Procedure D

7-Methoxyl-2-[N-butyonitrile-(N-(4-phenylpiperazin-1-yl)-butyl)amino]tetralin6a

A mixture of 5b (1.38 g, 3.51 mmol), 4-bromobutyonitrile (1.39 g, 8.78mmol), K₂CO₃ (5.0 g) and Et₃N (1.0 mL) was stirred in DMF (25 mL) at 60°C. under N₂ overnight. The mixture was diluted with water and extractedwith diethyl ether. The combined organic phase was dried over Na₂SO₄ andevaporated to give crude product, which was purified by flashchromatography (EtOAc/Hexane/Et₃N=100/100/1) to give thick oil 6a 1.51 g(93%). ¹H NMR (CDCl₃) 1.47-1.62 (m, 7H), 1.77-1.81 (t, J=6.6 Hz, 2H,CH₂CN), 1.96-2.00 (m, 1H), 2.39-2.44 (t, J=7.2 Hz, 2H, NCH₂), 2.44-2.49(t, J=7.0 Hz, NCH₂), 2.52-2.56 (t, 6.8 Hz, 2H, NCH₂), 2.61-2.64 (t,J=5.0 Hz, 4H, N(CH₂)₂), 2.73-2.93 (m, 5H), 3.21-3.24 (t, J=4.8 Hz, 4H,N(CH₂)₂), 3.77 (s, 3H, CH₃O), 6.63-6.71 (m, 2H, Ar—H), 6.84-7.01 (m, 4H,Ar—H), 7.25-7.30 (m, 2H, Ar—H).

7-Methoxyl-2-[N-acetonitrile-(N-(4-phenylpiperazin-1-yl)-butyl)amino]tetralin6b

A mixture of 5b (0.63 g, 1.60 mmol) was reacted with bromoacetonitrile(0.50 g, 4.17 mmol), K₂CO₃ (2.20 g) in Et₃N (1.0 mL) and DMF(25 mL) togive a thick oil 6b, 0.53 g (76%) (Procedure D). ¹H NMR (CDCl₃)1.52-1.81 (m, 4H), 2.09-2.17 (m, 2H), 2.40-2.44 (t, J=6.3 Hz, 2H),2.60-2.63 (t, J=4.6 Hz, 4H, N(CH₂)₂), 2.74-2.88 (m, 5H), 2.89-2.99 (m,2H), 3.31-3.35 (t, J=4.8 Hz, 4H, N(CH₂)₂), 3.67 (s, 2H, CH₂CN), 3.77 (s,3H, CH₃O), 6.61-6.71 (m, 2H, Ar—H), 6.85-6.97 (m, 4H, Ar—H), 7.24-7.29(m, 2H, Ar—H).

Procedure E

7-Methoxy-1-2-[N-(4-aminobutyl)-(N-(4-phenylpiperazin-1-yl)-butyl)amino]-tetralin7a

Dry THF (5 mL) wad added dropwise into lithium aluminum hydride (LAH)(0.13 g, 3.68 mmol) in ice bath under N₂. Compound 6a (0.30 g, 0.65mmol) in dry THF (15 mL) was added dropwise into above LAH/THFsuspension. The reaction mixture was refluxed for 8 h. After thereaction mixture was cooled to room temperature, saturated NaOH/H₂O (1mL) was added dropwise. The mixture was filtered and the solution wasdried over Na₂SO₄. The solvent was removed under vacuo to give a whitesolid 7a, 0.30 g (97%). ¹H NMR (CDCl₃) 1.56-1.90 (m, 8H), 2.03-2.08 (m,2H), 2.46-2.51 (t, J=7.2 Hz, 2H), 2.61-2.67 (m, 4H), 2.67-2.70 (t, J=4.8Hz, 4H, N(CH₂)₂), 2.77-2.93 (m, 6H), 3.03-3.10 (m, 1H), 3.27-3.30 (t,J=4.8 Hz, 4H, N(CH₂)₂), 3.77 (s, 3H, CH₃O), 6.63-6.70 (m, 2H, Ar—H),6.83-6.94 (m, 4H, Ar—H), 7.24-7.29 (m, 2H, Ar—H).

7-Methoxy-1-2-[N-(2-aminoethyl)-(N-(4-phenylpiperazin-1-yl)-butyl)amino]-tetralin7b

Compound 6b (0.37 g, 0.86 mmol) was reacted with LAH (0.23 g, 7.60 mmol)in dry THF (20 mL) to give a white solid 7b, 0.35 g (95%) (Procedure E).¹H NMR (CDCl₃) 1.54-1.65 (m, 4H), 2.09-2.13 (m, 2H), 2.39-2.44 (t, J=7.2Hz, 2H), 2.59-2.63 (m, J=4.5 Hz, 4H, N(CH₂)₂), 2.74-2.89 (m, 10H),3.02-3.06 (m, 1H), 3.19-3.22 (t, J=4.8 HZ, 4H, N(CH₂)₂), 3.77 (s, 3H,CH₃O), 6.63-6.71 (m, 2H, Ar—H), 6.83-6.92 (m, 4H, Ar—H), 7.25-7.30 (m,2H, Ar—H).

Procedure F

7-Hydroxy-2-[N-butyonitrile-(N-(4-phenylpiperazin-1-yl)-butyl)amino]tetralin8

Compound 6a (0.29 g, 0.63 mmol) was dissolved in dry CH₂Cl₂ (10 mL). Thesolution was cooled to −40° C. by dry ice. The solution of 1MBBr₃/CH₂Cl₂ (1.0 mL) was added slowly. The reaction mixture was stirredat −40° C. for 2 h and then at room temperature overnight. SaturatedNaHCO₃/H₂O was added and the mixture was extracted by CH₂Cl₂. Thecombined organic phase was dried over Na₂SO₄. After the solvent wasremoved under vacuo, the crude product was purified with flashchromatography (EtOAc/Et₃N=50/1) to give compound 8, 0.18 g (65%). ¹HNMR (CDCl₃) 1.47-1.61 (m, 8H), 1.75-1.79 (t, J=6.6 Hz, 2H, CH₂CN),1.94-1.97 (m, 2H), 2.39-2.47 (m, 4H), 2.49-2.54 (t, J=6.3 Hz, 2H, NCH₂),2.61-2.64 (t, J=5.1 Hz, 4H, N(CH₂)₂), 2.69-2.91 (m, 5H), 3.20-3.23 (t,J=4.5 Hz, 4H, N(CH₂)₂), 6.54-6.60 (m, 2H, Ar—H), 6.83-6.95 (m, 3H,Ar—H), 7.24-7.29 (m, 2H, Ar—H). Free base was converted into its HBrsalt. m.p.=171-175° C. Anal. (C₂₈H₃₈N₄0.3HBr) Cacl: C, 49.94; H, 6.14;N, 8.32; Found: C, 49.94; H, 6.28; N, 8.29.

Procedure G

7-Methoxyl-2-[N-(4-benzoylaminobutyl)-(N-(4-phenylpiperazin-1-yl)-butyl)amino]tetralin9a

Benzoic acid (0.10 g, 0.78 mmol),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.14 g,0.71 mmol) and 1-hydroxybenzotriazole (0.11 g, 0.78 mmol) were dissolvedin dry CH₂Cl₂ (10 mL). The solution was stirred at room temperature for0.5 h. 7a (0.30 g, 0.65 mmol) in CH₂Cl₂ (10 mL) was added into the abovesolution. The reaction mixture was stirred at room temperatureovernight. The solvent was evaporated and H₂O (50 mL) was added. Themixture was extracted with EtOAc. The organic phase was dried overNa₂SO₄. After evaporation, the crude product was purified with flashchromatography (EtOAc/Et₃N=50/1) to give compound 9, 0.26 g (71%). ¹HNMR (CDCl₃) 1.52-1.67 (m, 8H). 1.97-2.05 (m, 2H), 2.36-2.41 (t, J=6.9Hz, 2H), 2.59-2.62 (t, J=4.8 Hz, 6H, N(CH₂)₂, NCH₂), 2.74-2.87 (m, 4H),2.97-3.07 (m, 1H), 3.18-3.22 (t, J=4.8 Hz, N(CH₂)₂), 3.46-3.52 (t, J=6.2Hz, 2H), 3.71 (s, 3H, CH₃O), 6.57-6.71 (m, 2H), 6.84-7.00 (m, 4H, Ar—H),7.25-7.27 (m, 2H, Ar—H), 7.40-7.52 (m, 3H, Ar—H), 7.77-7.79 (d, J=7.9Hz, 2H).

7-Methoxyl-2-[N-(2-benzoylamino)ethyl-(N-(4-phenylpiperazin-1-yl)-butyl)amino]tetralin9b

Compound 7b (0.35 g, 0.84 mmol) was reacted with benzonic acid (0.12 g,1.02 mmol),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide-hydrochloride (0.19 g,0.10 mmol) and 1-hydroxybenzotriazole (0.14 g, 1.01 mmol) in CH₂Cl₂ (20mL) to give compound 9b, 0.30 g (69%) (Procedue G). ¹H NMR (CDCl₃)1.53-1.61 (m, 4H), 1.97-2.05 (m, 2H), 2.34-2.38 (t, J=6.2 Hz, 2H),2.53-2.42 (t, J=4.2 Hz, 4H, N(CH₂)₂), 2.59-2.62 (m, 2H), 2.73-2.81 (m,6H), 3.03-3.05 (m, 1H), 3.13-3.16 (t, J=4.5 Hz, 4H, N(CH₂)₂), 3.48-3.52(m, 2H), 3.76 (s, 3H, CH₃O), 6.59-6.68 (m, 2H, Ar—H), 6.85-7.00 (m, 4H,Ar—H), 7.24-7.28 (m, 2H, Ar—H), 7.42-7.51 (m, 3H, Ar—H), 7.78-7.80 (d,J=6.9 Hz, 2H, Ar—H).

7-Hydroxyl-2-[N-(4-benzoylaminobutyl)-(N-(4-phenylpiperazin-1-yl)-butyl)amino]tetralin10a

Compound 9a (0.17 g, 0.30 mmol) was reacted with 1.0 M BBr₃/CH₂Cl₂ (1.5mL) to give compound 10a, 0.12 g (72%) (Procedure F). m.p.=70-71° C. ¹HNMR (CDCl₃) 1.52-1.69 (m, 8H), 1.97-2.05 (m, 2H), NCH₂), 2.54-2.61 (m,6H, N(CH₂)₂), 2.71-2.84 (m, 4H), 2.36-2.41 (t, J=6.9 Hz, 2H), 2.95-3.05(m, 1H, NCH), 3.18-3.21 (t, J=4.6 Hz, 4H, N(CH₂)₂), 3.45-3.51 (t, J=6.2Hz, 2H), 6.52-6.61 (m, Ar—H, 2H), 6.83-6.88 (m, 4H, Ar—H), 7.24-7.29 (m,2H, Ar—H), 7.39-7.49 (m, 3H, Ar—H), 7.76-7.79 (d, J=7.2 Hz, 2H, Ar—H)Anal. C₃₅H₄₆N₄O₂.0.22H₂O, Cacl: C, 75.26; H, 8.37; N, 10.01; Found: C,75.23; H, 8.28; N, 9.75.

7-Hydroxy-2-[N-(2-benzoylamino)ethyl-(N-(4-phenylpiperazin-1-yl)-butyl)amino]tetralin10b

Compound 9b (0.28 g, 0.53 mmol) was reacted with 1M BBr₃/CH₂Cl₂ (2.0 mL,2.0 mmol) to give compound 10b, 0.21 g(76%) (Procedure F). m.p.=68-69°C. ¹H NMR (CDCl₃) 1.54-1.70 (m, 4H), 1.89-2.05 (m, 2H), 2.35-2.39 (t,J=4.9 Hz, 2H), 2.53-2.56 (t, J=4.2 Hz, 4H, N(CH₂)₂), 2.61-2.67 (m, 2H),2.72-2.98 (m, 6H), 2.99-3.07 (m, 2H), 3.14-3.17 (t, J=4.5 Hz, 4H,N(CH₂)₂), 3.45-3.53 (m, 2H), 6.51-6.61 (m, 2H, Ar—H), 6.86-6.92 (m, 4H,Ar—H), 7.24-7.29 (m, 2H, Ar—H), 7.42-7.51 (m, 3H, Ar—H), 7.79-7.81 (d,J=6.9 Hz, 2H, Ar—H). Anal. (C₃₅H₄₈N₄O₂.0.22H₂O) Cacl: C, 74.75; H, 8.05;N, 10.56; Found, C, 74.80; H, 8.22; N, 10.03.

7-Methoxyl-2-[N-propargyl-(N-(4-phenylpiperazin-1-yl)-ethyl)amino]tetralin11a

Compound 5a (1.18 g, 3.04 mmol) was reacted with propargyl chloride(1.20 g, 16.11 mmol) in the presence of K₂CO₃ (4.0 g) and DMF (25 mL) at60° C. for 5 h to furnish 11a, 0.35 g (29%) (Procedure D). ¹HNMR (CDCl₃)1.59-1.71 (m, 2H), 2.13-2.18 (m, 2H), 2.20-2.34 (t, J=2.1 Hz, 1H, C≡CH),2.56-2.60 (t, J=6.9 Hz, 2H, NCH₂), 2.65-2.68 (t, J=4.8 Hz, 4H, N(CH₂)₂),2.75-2.81 (m, 2H), 2.84-2.89 (t, J=7.2 Hz, 2H). 2.98-3.02 (m, 3H),3.20-3.23 (t, J=4.8 Hz, 4H, N(CH₂)₂), 3.60 (s, 2H, NCH ₂C≡CH), 3.77 (s,3H, CH₃O), 6.60-6.83 (m, 2H, Ar—H), 6.85-6.98 (m, 4H, Ar—H), 7.23-7.29(m, 2H, Ar—H).

7-Methoxy-2-[N-propargyl-(N-(4-phenylpiperazin-1-yl)-butyl)amino]tetralin11b

A mixture of 5b (0.65 g, 1.65 mmol), propagyl chloride (0.30 mL, 4.63mmol), K₂CO₃ (1.0 g) and Et₃N (1.0 mL) was stirred in DMF (20 mL) at 60°C. under N₂ for 5 h to give a thick oil 11b, 0.33 g (46%) (Procedure D).¹H NMR (CDCl₃) 1.51-1.56 (m, 4H), 2.11-2.15 (m, 2H), 2.17-2.19 (t, J=2.2HZ, 1H, C≡CH), 2.40-2.44 (t, J=7.2 Hz, 2H), 2.59-2.63 (t, J=4.8 Hz, 4H,N(CH₂)₂), 2.67-2.83 (m, 5H), 2.93-3.01 (m, 2H), 3.19-3.23 (t, J=4.5 HZ,4H, N(CH₂)₂), 3.52-3.53 (d, J=2.1 Hz, 2H, CH₂CECH), 3.77 (s, 3H, CH₃O),6.62-6.70 (m, 2H, Ar—H), 6.83-7.00 (m, 4H, Ar—H), 7.24-7.29 (m, 2H,Ar—H).

7-Hydroxy-1-2-[N-propargyl-(N-(4-phenylpiperazin-1-yl)-ethyl)amino]tetralin12a

Compound 11a (0.28 g, 0.70 mmol) was reacted with 1M BBr₃/CH₂Cl₂ (1.50mL, 1.50 mmol) in CH₂Cl₂ (15 mL) to furnish 12a, 0.23 g (84%) (ProcedureE). ¹HNMR (CDCl₃) 1.56-1.68 (m, 2H), 2.11-2.15 (m, 2H), 2.20-2.22 (t,J=2.1 Hz, 1H, C≡CH), 2.57-2.61 (t, J=6.6 Hz, 2H, NCH₂), 2.65-2.69 (t,J=4.8 Hz, 4H, N(CH₂)₂), 2.75-2.81 (m, 2H), 2.86-2.91 (t, J=4.8 Hz, 2H,N(CH₂)₂), 3.58 (s, 2H, CH₂ CH ₂C≡CH), 6.55-6.61 (m, 2H, Ar—H), 6.83-6.94(m, 4H, Ar—H). 7.23-7.27 (m, 2H, Ar—H). Free base was converted into itsHCl salt. m.p.=164-166° C. Anal. (C₂₇H₃₁N₃O.3HCl.0.8H₂O) Calcd. C,58.49; H, 6.98; N, 8.18; Found: C, 58.58; H, 6.77; N, 8.05.

7-Hydroxy-2-[N-propargyl-(N-(4-phenylpiperazin-1-yl)-butyl)amino]tetralin12b

Compound 11b (0.195 g, 0.742 mmol) was reacted with 1M BBr₃/CH₂Cl₂ (0.80mL, 0.80 mmol) to give compound 12b, 0.13 g (72%). ¹HNMR (CDCl₃)1.54-1.68 (m, 4H), 2.09-2.14 (m, 2H), 2.17-2.18 (t, J=2.1 Hz, 1H),2.41-2.45 (t, J=7.0 Hz, 2H), 2.60-2.63 (t, J=4.5 Hz, 4H, N(CH₂)₂),2.67-2.71 (t, J=6.2 Hz, 2H), 2.76-2.80 (m, 3H), 2.89-2.92 (m, 1H)3.51-3.52 (d, J=2.1 Hz, 2H, CH ₂C≡CH), 3.20-3.24 (t, J=4.6 Hz, 4H,N(CH₂)₂), 6.56-6.61 (m, 2H, Ar—H), 6.88-6.95 (m, 4H, Ar—H), 7.24-7.29(m, 2H, Ar—H),). Free base was converted into its HBr salt.m.p.=182-186° C. Anal. (C₂₇H₃₅N₃O.3HBr.0.75H₂O). Cacl: C, 48.12; H,5.87; N, 6.24; Found: C, 48.12; H, 5.86; N, 6.20.

Procedure H

7-Methoxyl-2-[N-propionyl-(N-(4-phenylpiperazin-1-yl)-ethyl)amino]tetralin13a

Compound 5a (0.36 g, 0.97 mmol) was dissolved in CH₂Cl₂ (10 mL) and Et₃N(1.0 mL). The solution was cooled in an ice bath, and propionyl chloride(0.20 g, 2.16 mmol) was added. After the reaction mixture was stirred atroom temperature for 2 h, TLC showed completion of the reaction. Thesolvent was removed under vacuo. The mixture was dissolved in EtOAc andwashed with H₂O. The organic phase was dried over Na₂SO₄. Theevaporation of the solution gave the crude product, which was purifiedby flash chromatography (EtOAc/MeOH/Et₃N=95/5/0.5) to give 13a, 0.42 g(93%) (Procedure F). ¹HNMR (CDCl₃) 1.14-1.20 (t, J=6.6 Hz, 3H, CH₃CH₂CO), 1.63-1.70 (m, 2H), 1.90-2.04 (m, 2H), 2.40-2.50 (m, 4H),2.66-2.74 (t, J=4.8 Hz, 4H, N(CH₂)₂) 2.76-2.91 (m, 5H), 3.20-3.22 (t,J=4.8 Hz, 4H, N(CH₂)₂), 3.78 (s, 3H, CH₃O), 6.60-6.70 (m, 2H, Ar—H),6.91-7.01 (m, 4H, Ar—H), 7.25-7.29 (m, 2H, Ar—H).

7-Methoxyl-2-[N-propionyl-(N-(4-phenylpiperazin-1-yl)-butyl)amino]tetralin13b

Compound 5b (0.28 g, 0.71 mmol) was reacted with propionyl chloride(0.25 g, 3.57 mmol) in CH₂Cl₂ (10 mL) and Et₃N (1.0 mL) to give purecompound 18, 0.32 g (99%). ¹H NMR (CDCl₃) 1.11-1.26 (t, J=6.6 Hz, 3H),1.52-1.74 (m, 5H), 1.89-1.98 (m, 1H), 2.35-2.45 (m, 4H), 2.58-2.61 (t,J=4.5 Hz, 4H, N(CH₂)₂), 2.78-3.05 (m, 4H), 3.18-3.23 (t, J=4.5 Hz, 4H,N(CH₂)₂), 3.15-3.56 (m, 1H), 3.76 (s, 3H, CH₃O—), 6.58-6.73 (m, 2H,Ar—H), 6.85-7.03 (m, 4H, Ar—H), 7.23-7.28 (t, J=7.6 Hz, 2H, Ar—H).

7-Methoxyl-2-[N-propyl-(N-(4-phenylpiperazin-1-yl)-ethyl)amino]tetralin14a

Compound 13a (0.38 g, 0.90 mmol) was reacted with LAH (0.15 g, 4.41mmol) in THF (25 mL) to furnish 14a, 0.36 g (97%) (procedure E). ¹HNMR(CDCl₃) 0.87-0.93 (t, J=7.2 Hz, 3H, CH ₃CH₂CH₂N), 1.46-1.53 (m, 4H),1.88-2.07 (m, 2H), 2.51-2.55 (t, J=7.2 Hz, 2H, CH₂N), 2.64-2.68 (t,J=4.8 Hz, 4H, N(CH₂)₂), 2.72-2.83 (m, 6H), 2.90-3.06 (m, 1H), 3.19-3.22(t, J=4.8 Hz, 4H, N(CH₂)₂), 3.77 (s, 3H, CH₃O), 6.62-6.70 (m, 2H, Ar—H),6.85-7.00 (m, 4H, Ar—H), 7.24-7.29 (m, 2H, Ar—H).

7-Methoxyl-2-[N-propyl-(N-(4-phenylpiperazin-1-yl)-butyl)amino]tetralin14b

Compound 13b (0.30 g, 0.71 mmol) was reacted with LAH (0.25 g, 7.57mmol) in THF (20 mL) to give 14b 0.28 g (99%) (procedure E). ¹H NMR(CDCl₃) 0.86-0.91 (t, J=7.2 Hz, 3H), 1.40-1.66 (m, 7H), 1.98-2.05 (m,1H), 2.38-2.43 (t, J=7.2 Hz, 2H), 2.45-2.50 (t, J=7.2 Hz, 2H), 2.52-2.56(t, J=6.8 Hz, 2H), 2.59-2.62 (t, J=4.8 Hz, 4H, N(CH₂)₂), 2.69-2.88 (m,4H), 2.91-3.02 (m, 1H), 3.20-3.22 (t, J=4.5 Hz, 4H, N(CH₂)₂), 3.77 (s,3H, CH₃O), 6.62-6.69 (m, 2H, Ar—H), 6.83-7.00 (m, 4H, Ar—H), 7.24-7.29(m, 2H, Ar—H).

7-Hydroxy-2-[N-propyl-(N-(4-phenylpiperazin-1-yl)-ethyl)amino]tetralin15a

Compound 14a (0.60 g, 0.88 mmol) was reacted with 1M BBr₃/CH₂Cl₂ (1.60mL, 1.60 mmol) in CH₂Cl₂ (20 mL) to furnish 15a, 0.29 g (83%) (ProcedureF). ¹H NMR (CDCl₃) 0.86-0.91 (t, J=7.2 Hz, 3H, CH ₃CH₂CH₂N), 1.43-1.50(m, 4H), 1.89-1.93 (m, 2H), 2.46-2.51 (t, J=7.5 Hz, 2H, NCH₂), 2.53-2.68(m, 6H), 2.70-2.74 (t, J=4.8 Hz, 4HN(CH₂)₂), 2.83-2.88 (m, 1H),3.23-3.26 (t, J=4.8 Hz, 4H, N(CH₂)₂), 6.45-6.56 (m, 2H, Ar—H), 6.83-6.93(m, 4H, Ar—H), 7.23-7.26 (m, 2H, Ar—H). Free base was converted into itsHCl salt, m.p.=143-146° C. Anal. (C₂₇H₃₅N₃O.3HCl.0.9H₂O) Calcd. C,57.83; H, 7.72; N, 8.09; Found: C, 57.88; H, 7.52; N, 7.90.

7-Hydroxyl-2-[N-propyl-(N-(4-phenylpiperazin-1-yl)-butyl)amino]tetralin15b

Compound 19 (0.30 g, 0.69 mmol) was reacted with 1M BBr₃/CH₂Cl₂ (1.3 mL)to give 20, 0.25 g (87%) (Procedure F). ¹H NMR (CDCl₃) 0.86-0.91 (t,J=7.2 Hz, 3H), 1.40-1.82 (m, 7H), 1.93-2.05 (m, 1H), 2.39-2.44 (t, J=7.2Hz, 2H), 2.44-2.50 (t, J=7.5 Hz, 2H), 2.56-2.51 (t, J=6.6 Hz, 2H),2.60-2.63 (t, J=4.2 Hz, 4H, N(CH₂)₂), 2.75-2.80 (m, 4H), 2.92-2.99 (m,1H), 3.20-3.23 (t, J=4.2 Hz, 4H, N(CH₂)₂), 6.54-6.60 (m, 2H, Ar—H),6.83-6.95 (m, 4H, Ar—H), 7.24-7.29 (m, 2H, Ar—H). Free base wasconverted into its HBr salt. m.p.=152-156° C. Anal.C₂₇H₄₂N₃OBr₃.0.30H₂O. Cacl: C, 48.42; H, 6.41; N, 6.27. Found: C, 48.10;H, 6.64; N, 6.11.

7-Methoxyl-2-[(N-(4-(2,3-dichlorophenyl)-piperazin-1-yl)-butyl)amino]tetralin17

Compound 17 was synthesized from 16 according to the procedures (A, Band C) (70%, 3 steps). ¹HNMR (CDCl₃) 1.58-1.64 (m, 4H), 2.04-2.10 (m,2H), 2.43-2.47 (t, J=6.6 Hz, 2H), 2.60-2.65 (m, 4H(N(CH₂)₂), 2.76-2.82(m, 5H), 2.93-2.98 (m, 2H), 3.02-3.08 (m, 4H, N(CH₂)₂), 3.77 (s, 3H,CH₃O), 6.62-6.71 (m, 2H, Ar—H), 6.94-7.01 (m, 2H, Ar—H), 7.14-7.16 (m,2H, Ar—H).

7-Methoxyl-2-[N-propanyl-(N-(4-(2,3-dichlorophenyl)-piperazin-1-yl)-butyl)amino]tetralin18a

Compound 18a was synthesized from 17 according to the procedure (H, E)in (92%, two steps). ¹HNMR (CDCl₃) 0.89-0.93 (t, J=7.2 Hz, 3H, CH ₃CH₂),1.47-1.61 (m, 6H), 2.02-2.05 (m, 2H), 2.44-2.49 (t, J=7.2 Hz, 2H, NCH₂),2.52-2.65 (m, 8H), 2.76-2.87 (m, 5H), 3.07-3.08 (bs, 4H, N(CH₂)₂), 3.77(s, 3H, CH₃O), 6.63-6.70 (m, 2H, Ar—H), 6.95-7.00 (m, 2H, Ar—H),7.14-7.19 (t, J=2.7 Hz, 2H, Ar—H).

7-Methoxyl-2-[N-propargyl-(N-(4-(2,3-dichlorophenyl)-piperazin-1-yl)-butyl)amino]tetralin18b

Compound 17 was reacted with propargyl chloride (1.50 g, 20.13 mmol) andK₂CO₃ (4.50 g) in DMF (20 mL) to give 18b, 0.48 g (24%). ¹HNMR (CDCl₃)1.55-1.68 (m, 4H), 2.11-2.15 (m, 2H), 2.17-2.18 (t, J=1.8 Hz, 1H, C≡CH),2.43-2.47 (t, J=6.6 Hz, 2H), 2.49-2.66 (bs, 4H, N(CH₂)₂), 2.68-2.88 (m,8H), 2.98-3.00 (m, 1H), 3.06-3.10 (bs, 4H, N(CH₂)₂), 3.52-3.53 (d, J=1.8Hz, 2H, CH2C≡CH), 3.77 (s, 3H, CH₃O), 6.30-6.72 (m, 2H, Ar—H), 6.94-7.00(m, 2H, Ar—H), 6.97-7.16 (m, 2H, Ar—H).

7-Hydroxy-2-[N-propyl-(N-(4-(2,3-dichlorophenyl)-piperazin-1-yl)-butyl)amino]tetralin19a

Compound 10 (0.36 g, 0.71 mmol) was reacted with 1M BBr₃/CH₂Cl₂ (1.5 mL,1.5 mmol) to give product 11 (0.29 g, 83%). ¹HNMR (CDCl₃) 0.85-0.90 (t,J=7.2 Hz, 3H, CH₃), 1.43-1.58 (m, 6H), 1.96-2.00 (m, 2H), 2.44-2.55 (m,6H, CH ₂NN(CH ₂)₂), 2.69-2.77 (m, 8H), 2.94-2.95 (m, 1H), 3.08-3.09 (bs,4H, N(CH₂)₂), 6.51-6.57 (m, 2H, Ar—H), 6.88-6.93 (m, 2H, Ar—H),7.09-7.15 (m, 2H, Ar—H). Free base was converted into its HCl salt,m.p.=155-159° C. Anal. Calcd. (C₂₇H₃₇N₃OCl₂.3HCl.0.8H₂O) C, 52.79; H,6.82; N, 6.84; Found: C, 52.50; H, 6.82; N, 6.84.

7-Hydroxy-2-[N-propargyl-(N-(4-(2,3-dichlorophenyl)-piperazin-1-yl)-butyl)amino]tetralin19b

Compound 18b (0.28 g, 0.70 mmol was reacted with 1M BBr₃/CH₂Cl₂ (1.50mL, 1.50 mmol) to give pure product 8, 0.23 g (84%). ¹HNMR (CDCl₃)1.48-1.56 (m, 4H), 2.09-2.13 (m, 2H), 2.17-2.18 (t, J=1.8 Hz, 1H, C≡CH),2.45-2.47 (t, J=6.6 Hz, 2H), 2.66-2.68 (bs, 4H, N(CH₂)₂), 2.71-2.80 (m,5H), 2.89-2.96 (m, 2H), 3.09-3.10 (bs, 4H, N(CH₂)₂), 3.51-3.52 (d, J=1.5Hz, 2H, CH ₂C≡CH), 6.57-6.61 (m, 2H, Ar—H), 6.92-6.98 (m, 2H, Ar—H),7.14-7.16 (m, 2H, Ar—H). Free base was converted into its HCl salt,m.p.=180-183° C. Anal. Calcd. (C₂₇H₃₃N₃OCl₂.2.70HCl.0.06H₂O) C, 55.34;H, 6.16; N, 7.18; Found: C, 55.42; H, 6.16; N, 7.10.

4-[N-(4-phenylpiperazin-1-yl)-ethylamino]-cyclohexanone ethylene ketal20

A mixture of amine 4a (2.21 g, 10.8 mmol), ketone (1.68 g, 10.8 mol) andNa(OAc)₃BH (3.24 g, 15.12 mmol) in HOAc (0.65 g, 10.8 mol) andClCH₂CH₂Cl (40 mL) was stirred at room temperature for overnight. Thereaction mixture was diluted with EtOAc (200 mL), washed with brine, anddried over Na₂SO₄. After the evaporation of the organic layer, the crudeproduct was purified by flash chromatograpy(EtOAc/MeOH/Et₃N=100/5/1) togive white solid 20, 3.55 g (91%). ¹H NMR (300 MHz, CD₃Cl) 1.52-1.56 (m,6H), 1.74-1.79 (m, 2H), 1.91-1.96 (m, 2H), 2.57-2.66 (m, 7H, N(CH₂)₂,CHNHCH₂), 2.80-2.84 (t, J=6.0 Hz, 2H), 3.14-3.18 (t, J=48 Hz, 4H,N(CH₂)₂), 3.90 (s, 4H, OCH₂CH₂O), 6.83-6.91 (m, 3H, Ar—H), 7.21-7.25 (m,2H, Ar—H).

4-[N-propyl-(N-(4-phenylpiperazin-1-yl)-ethyl)amino]-cyclohexanoneethylene ketal 21

A mixture of amine 20 (1.0 g, 2.94 mmol), 1-bromopropane (1.45 g, 11.80mol) and K₂CO₃ (1.22 g, 8.70 mmol) in dry DMF(20 mL) was stirred at 60°C. for 10 h. The mixture was poured into water (50 mL) and extractedwith Et₂O (3×100 mL). The combined organic layer was washed with brineand dried over Na₂SO₄. After the evaporation of the organic solvent, theresidue was purified by flash chromatograpy(EtOAc/MeOH/Et₃N=100/2/1) togive a thick oil 21 0.80 g (70%). ¹H NMR (300 MHz, CD₃Cl) 0.83-0.88 (t,J=7.2 Hz, 3H, CH₃), 1.40-1.47 (m, 2H), 1.52-1.58 (m, 4H), 1.73-1.80 (m,4H), 2.41-2.50 (m, 4H), 2.58-2.65 (m, 7H), 3.17-3.20 (t, J=5.2 Hz, 4H,N(CH₂)₂), 3.17-3.20 (t, J=5.2 Hz, 4H, N(CH₂)₂), 3.92 (s, 4H, OCH₂CH₂O),6.82-6.86 (t, J=7.2 Hz, 1H, Ar—H), 6.90-6.93 (d, J=7.8 Hz, 2H, Ar—H),7.22-7.28 (m, 2H, Ar—H).

4-[N-propyl-(N-(4-phenylpiperazin-1-yl)-ethyl)amino]-cyclohexanone 22

A solution of ketal 21 (2.00 g, 5.17 mmol) in THF (20 mL) and 1N HCl (20mL) was stirred at 80° C. under N₂ for 2 h. THF was removed under vacuoand solid NaHCO₃ was added slowly extracted with EtOAc(3×100 mL). Thecombined organic layer was washed with brine and dried over Na₂SO₄. Theevaporation gave the crude product, which was purified by flashchromatograpy(EtOAc/Et₃N=100/1) to give 22, 1.31 g(99%). ¹H NMR (300MHz, CD₃Cl) 0.87-0.90 (t, J=5.7 Hz, 3H, CH₃), 1.43-1.51 (dt, J=5.7, 6.0Hz, 2H, NCH₂ CH ₂CH₃), 1.70-1.79 (m, 2H), 2.04-2.07 (m, 2H), 2.30-2.52(m, 8H), 2.64-2.70 (m, 6H), 2.97-3.03 (t, J=10.4 Hz, 1H, NCH(CH₂)₂),3.19-3.21 (t, J=4.4 Hz, 4H, N(CH₂)₂), 6.83-6.87 (t, J=7.2 Hz, 1H, Ar—H),6.91-6.93 (d, J=8.0 Hz, 2H, Ar—H), 7.24-7.28 (m, 2H, Ar—H).

2-Amino-6-[N-propyl-(N-(4-phenylpiperazin-1-yl)-ethyl)amino]-5,6,7,8-tetrahydrobenzopyrimidine23

To a solution of ketone 22 (0.60 g, 1.75 mmol) in dry toluene (20 mL)was added tris(dimethylamino)methane (1.27 g, 8.76 mmol), and themixture stirred under nitrogen at 90° C. for 4 h. The solvent wasremoved under vacuo, and the residue was dissolved in EtOH (25 mL).Guandine carbonate (0.78 g, 4.33 mmol) was added, and the mixture washeld at reflux for 17 h. The solvent was evaporated, and the residuediluted with CH₂Cl₂ and washed with brine. The organic layer was driedover Na₂SO₄ and evaporated to give the crude product, which was purifiedby flash chromatograpy (EtOAc/MeOH/Et₃N=25/1/1) to give a yellow solid23, 0.61 g(88%). ¹H NMR (300 MHz, CD₃Cl) 0.86-0.91 (t, J=7.2 Hz, 3H,CH₃), 1.44-1.52 (dt, J=7.2, 7.2 Hz, 2H, NCH₂ CH ₂CH₃), 1.61-1.74 (m,1H), 2.03-2.10 (m, 1H), 2.49-2.56 (m, 4H), 2.64-2.67 (t, J=5.0 Hz, 4H,N(CH₂)₂), 2.69-2.75 (m, 4H), 2.79-2.81 (dd, J=2.8, 6.0 Hz, 1H),2.85-2.95 (m, 1H), 3.18-3.21 (t, J=5.0 Hz, 4H, N(CH₂)₂), 4.88 (s, 2H,NH₂), 6.82-6.87 (t, J=7.2 Hz, 1H, Ar—H), 6.90-6.93 (d, J=8.4 Hz, 2H,Ar—H), 8.01 (s, 1H, H-pyrimidine). Free base was converted into HClsalt. m.p.=97-102° C. Anal: (C₂₃H₃₄N₆.5HCl.0.2H₂O) Cacl: C, 47.90, H,6.85; N, 14.47; Found: C, 48.36, H, 7.38; N, 14.48.

2-Bromo-4-[N-propyl-(N-(4-phenylpiperazin-1-yl)-ethyl)amino]-cyclohexanone24

Into the solution of ketone 22 (0.86, 2.51 mmol) in HOAc (50 mL) and 40%HBr/HOAc(w/v) (3.0 mL) was added Bromine (0.45 g, 2.81 mmol) in HOAc (10mL) dropwise. The white solid was precipitated after several minutes.The mixture was stirred for 1 h and the most of solvent was removedunder vacuo. The solid was collected with filtration and dried undervacuo to give 1.45 g(87%).

2-Amino-5-[N-propyl-(N-(4-phenylpiperazin-1-yl)-ethyl)amino]-4,5,6,7-tetrahydrobenzothiazole25

A solution of bromide HBr salt 24 (0.99 g, 1.49 mmol), thiourea (0.14 g,179 mmol) in EtOH (50 mL) was refluxed for 2 h. The solvent was removedunder vacuo. The residue was diluted with EtOAc and solid NaHCO₃ wasadded. The mixture was filtered and the organic layer was evaporated togive crude product, which was purified with flash chromatography(EtOAc/Et₃N=100/1) to give pure compound 25, 140 mg. ¹H NMR (300 MHz,CD₃Cl) 0.87-0.91 (t, J=8.0 Hz, 3H, CH₃), 1.43-1.52 (h, J=7.2 Hz, 2H, CH₃CH ₂CH₂N), 1.69-1.79 (dq, J=4.8, 12.8 Hz, 2H), 1.86 (bs, 2H, NH₂),2.04-2.30 (m, 2H), 2.30-2.38 (dt, J=6.0, 13.6 Hz, 2H), 2.42-2.52 (m,6H), 2.64-7.71 (m, 6H), 2.97-3.03 (dt, J=3.4, 8.0 Hz, 1H), 3.19-3.21 (t,J=5.2 Hz, 4H, N(CH₂)₂), 6.83-6.87 (t, J=7.2 Hz, 1H, Ar—H), 6.91-6.93 (d,J=8.0 Hz, 2H, Ar—H), 7.24-7.28 (m, 2H, Ar—H).

2-(4-Nitro-phenyl)-N-[2-(4-phenyl-piperazin-1-yl)-ethyl]-acetamide (26a)

To a stirred solution of 2-(4-Phenyl-piperazin-1-yl)-ethylamine 4a (0.5g, 2.44 mmol) and Et₃N (0.34 g, 3.41 mmol) in 40 mL of dry CH₂Cl₂ undernitrogen at 0° C. was added a solution (4-Nitro-phenyl)-acetyl chloride(0.58 g, 2.92 mmol). The temperature was allowed to rise to roomtemperature, the mixture was stirred for 2 h, and then washed withwater. The aqueous layer was extracted with dichloromethane. Thecombined organic phase was washed with saturated sodium chloride, dried(Na₂SO₄) and concentrated. The crude product was purified by columnchromatography over silica gel (EtOAc) to produce 26a: 0.8 g, (89%yield) as a white solid (mp: 138-139° C.). ¹H NMR (CDCl₃, 400 MHz): δ2.52 (2H, t, J=5.6, CH₂—CH₂NH), 2.57 (4H, t, J=5.2, (CH₂)₂N—), 3.11 (4H,t, J=5.2, (CH₂)₂—NPh), 3.36-3.34 (2H, m, CH₂—NHCO), 3.65 (2H, s, CH₂Ar),6.19 (1H, bs, NHCO), 6.86-6.91 (3H, m, ArH), 7.25-7.29 (2H, m, ArH),7.47 (2H, d, J=8.8, ArH), 8.16-8.19 (2H, m, ArH).

2-(3-nitro-phenyl)-N-[2-(4-phenyl-piperazin-1-yl)-ethyl]-acetamide(26b): (Procedure same as 26a)

2-(4-Phenyl-piperazin-1-yl)-ethylamine 4a (0.5 g, 2.43 mmol) was reactedwith (3-Nitro-phenyl)-acetyl chloride (0.58 g, 2.92 mmol) in dichloromethane to give a crude product, which was purified by chromatography(EtOAc/Hexane=9/1) to produce 26b: 0.83 g (92% yield) as a yellow solid(mp: 115-116° C.). ¹H NMR (CDCl₃, 400 MHz): δ 2.51-2.57 (6H, m,(CH₂)₃N), 3.06-3.14 (4H, m, (CH₂)₂NPh), 3.36-3.39 (2H, m, CH₂—NHCO),3.65 (2H, s, CH₂Ar), 6.16 (1H, bs, NHCO), 6.85-6.91 (2H, m, ArH),7.25-7.29 (3H, m, ArH), 7.50 (1H, t, J=8.4, ArH), 7.65 (1H, d, J=7.6,ArH). 8.11-8.15 (2H, m, ArH).

[2-(4-nitro-phenyl)-ethyl]-[2-(4-phenyl-piperazin-1-yl)-ethyl]-amine(27a)

To a stirred solution of NaBH₄ (0.449 g, 11.81 mmol) in 50 mL of dry THFat 0° C. under N₂ was added dropwise 48% w/w BF₃ ether complex (1.47 mL,11.68 mmol). The cooling bath was removed and the solution was stirredfor 1 h at room temperature. Into the above was added dropwise asolution of2-(4-nitro-phenyl)-N-[2-(4-phenyl-piperazin-1-yl)-ethyl]-acetamide 26a(0.55 g, 1.49 mmol) dissolved in THF (5 mL). The reaction mixture wasrefluxed for 6 h. After the solution cooled to room temperature,methanol (5 mL) was added slowly. The solvent was removed under reducedpressure and 10% HCl/MeOH (25 mL) was added to the residue and thesolution refluxed for 1 h. Solid NaHCO₃ was added and methanol wasremoved in vacuo. The mixture was extracted with EtOAc. The combinedorganic phase was dried over Na₂SO₄ and evaporated to give the crudeproduct which was purified by chromatography (EtOAc/MeOH=4/1) to give27a: 0.385 g (73% yield) as a colorless oil. ¹H NMR (CDCl₃, 400 MHz): δ1.62 (1H, bs, NH), 2.50 (2H, t, J=5.6 Hz, CH₂—CH₂NH), 2.58 (4H, t, J=4.8Hz, (CH₂)₂N), 2.76 (2H, t, J=5.6 Hz, CH₂Ar), 2.90-2.96 (4H, m,(CH₂)₂NH), 3.14 (4H, t, J=4.8 Hz, (CH₂)₂NPh), 6.85 (1H, t, J=7.2, ArH),6.90 (2H, d, J=9.2, ArH), 7.25 (2H, t, J=9.2, ArH), 7.37 (2H, d, J=8.8,ArH), 8.15 (2H, d, J=8, ArH).

[2-(4-nitro-phenyl)-ethyl]-[2-(4-phenyl-piperazin-1-yl)-ethyl]-amine(27b): (Procedure same as 27a)

2-(3-nitro-phenyl)-N-[2-(4-phenyl-piperazin-1-yl)-ethyl]-acetamide 26b(0.53 g, 1.43 mmol) was reacted with the stirred solution of NaBH₄(0.433 g, 11.39 mmol) and 48% w/w BF₃ ether complex (1.42 ml, 11.28mmol) in dry THF to produce a crude product, which was purified bychromatography (EtOAc)/MeOH=4/1) to give 27b: 0.375 g (74% yield) as acolorless oil. ¹H NMR (CDCl₃, 400 MHz): δ 1.62 (1H, bs, NH), 2.52-2.59(6H, m, (CH₂)₂N), 2.77 (2H, t, J=5.6, CH₂Ar), 2.90-2.98 (4H, m,(CH₂)₂NH), 3.13 (4H, t, J=5.6, (CH₂)₂NPh), 6.85 (1H, t, J=7.2, ArH),6.90 (2H, d, J=8.4 Hz, ArH), 7.2 (2H, t, J=9.2, ArH), 7.45 (1H, t, J=8Hz, ArH), 7.55 (1H, d, J=7.2 Hz, ArH), 8.05 (1H, d, J=8 Hz, ArH), 8.09(1H, s, ArH).

N-[2-(4-Nitro-phenyl)-ethyl]-N-[2-(4-phenyl-piperazin-1-yl)-ethyl]-propionamide(28a)

To a stirred solution of[2-(4-nitro-phenyl)-ethyl]-[2-(4-phenyl-piperazin-1-yl)-ethyl]-amine 27a(0.375 g, 1.05 mmol), Et₃N (0.267 g, 2.64 mmol) in 25 mL of dry CH₂Cl₂under nitrogen at 0° C. was added a solution of propionyl chloride(0.137 g, 1.48 mmol). The temperature was allowed to rise to roomtemperature, the mixture stirred for 2 h, and then washed with water.The aqueous layer was extracted with dichloromethane. The combinedorganic phase was dried (Na₂SO₄) and concentrated. The crude product waspurified by column chromatography over silica gel (EtOAc/Hex=9/1) togive 28a as a colorless oil: 0.39 g (89% yield). ¹H NMR (CDCl₃, 400MHz): δ 1.16 (3H, t, J=7.2, CH₃), 2.38 (2H, q, J=7.2, CH₂), 2.51 (2H, t,J=7.2 Hz, CH₂Ar), 2.62 (4H, t, J=4.8, (CH₂)₂N), 2.99 (2H, t, J=7.2,CH₂—CH₂NCO), 3.15-3.20 (4H, m, (CH₂)₂NHPh, 3.32 (2H, t, J=7.2,CH₂—CH₂Ar), 3.58 (2H, t, J=7.2, CH₂NCO), 6.83-6.93 (3H, m, ArH),7.23-7.28 (2H, m, ArH), 7.34 (1H, d, J=8.0, ArH), 7.38 (1H, d, J=8.8,ArH, 8.15 (1H, d, J=8.8, ArH), 8.18 (1H, d, J=8.4, ArH).

N-[2-(3-nitro-phenyl)-ethyl]-N-[2-(4-phenyl-piperazin-1-yl)-ethyl]-propionamide(28b): (Procedure same as 28a)

[2-(4-nitro-phenyl)-ethyl]-[2-(4-phenyl-piperazin-1-yl)-ethyl]-amine 27b(0.375 g, 1.05 mmol) was reacted with propionyl chloride (0.137 g, 1.48mmol) in presence of Et₃N (0.267 g, 2.64 mmol) in dry CH₂Cl₂ to producea crude product, which was purified by chromatography (EtOAc/Hex=9/1) togive 28b: 0.398 g (92% yield) as a colorless oil. ¹H NMR (CDCl₃, 400MHz): δ 1.16 (3H, t, J=7.2 Hz, CH₃), 2.38 (2H, q, J=7.2 Hz, CH₂), 2.52(2H, t, J=7.2 Hz, CH₂Ar), 2.62 (4H, t, J=4.8 Hz, (CH₂)₂N), 2.99 (2H, t,J=7.2 Hz, CH₂—CH₂NCO), 3.16-3.21 (4H, m, (CH₂)₂NHPh, 3.34 (2H, t, J=7.2Hz, CH₂—CH₂Ar), 3.59 (2H, t, J=7.2 Hz, CH₂NCO), 6.83-6.88 (1H, m, ArH),6.91 (2H, d, J=8 Hz, ArH), 7.23-7.30 (2H, m, ArH), 7.44-7.60 (2H, mArH), 8.07-8.13 (2H, m, ArH).

4-(2-{[2-(4-Phenyl-piperazin-1-yl)-ethyl]-propyl-amino}-ethyl)-phenylamine(29a)

N-[2-(4-nitro-phenyl)-ethyl]-N-[2-(4-phenyl-piperazin-1-yl)-ethyl]-propionamide28a (0.33 g, 0.80 mmol) was dissolved in dry EtOH (20 mL) and 10 wt %Pd/C (0.05 g) was added. The mixture was stirred for overnight under H₂at 1 atm. Pressure. The reaction mixture was filtered through celite andfiltrate was concentrated under reduced pressure and kept under vacuumfor 1 h to give the corresponding aniline. In to the solution of thecrude product in 15 ml dry THF was added 1(M) BH₃/THF (7 mL, 7 mmol).The reaction mixture was refluxed for 6 h. After the solution was cooledto room temperature, methanol (5 mL) was added slowly. The solvent wasremoved under reduced pressure and 10% HCl/MeOH (25 mL) was added intothe residue and the solution was refluxed for 1 h. Solid NaHCO₃ wasadded and the methanol was removed in vacuo. The mixture was extractedwith EtOAc. The combined organic phase was dried over Na₂SO₄ andevaporated to give the crude product which was purified bychromatography (EtOAc/MeOH=9/1) to give 29a as a colorless oil: 0.23 g(78% yield). ¹H NMR (CDCl₃, 300 MHz): δ 0.89 (3H, t, J=7.2 Hz, CH₃),1.50 (2H, q, J=7.2 Hz, CH₂), 2.48-2.57 (4H, m, CH₂Ar, (CH₂)N), 2.63-2.75(10H, m, (CH₂)₃N, (CH₂)₂N), 3.20 (4H, t, J=4.8 Hz, (CH₂)₂NPh), 3.56 (2H,bs, NH₂), 6.62 (2H, d, J=8.7 Hz, ArH), 6.85 (1H, t, J=9.6 Hz, ArH),6.91-6.99 (4H, m, ArH), 7.25 (2H, t, J=9 Hz, ArH). Free base wasconverted into its hydrochloride salt, mp 262-264° C. Elemental analysiscalculated for C₂₃H₃₈N₄Cl₄,1.05H₂O:C, 51.99; H, 7.60; N, 10.54. Found C,52.37; H, 7.89; N, 10.12.

3-(2-{[2-(4-Phenyl-piperazin-1-yl)-ethyl]-propyl-amino}-ethyl)-phenylamine(29b): (Procedure same as 29a)

N-[2-(3-nitro-phenyl)-ethyl]-N-[2-(4-phenyl-piperazin-1-yl)-ethyl]-propionamide28b (0.33 g, 0.80 mmol) was reacted with H₂ in presence of 10 wt % Pd/C(0.05 g) to produce corresponding aniline, which was then reacted with1(M) BH₃/THF (7 ml, 7 mmol) to produce a crude product. The crudeproduct was purified by chromatography (EtOAc/MeOH=9/1) to give 29b as acolorless oil 0.248 g (81% yield). ¹H NMR (CDCl₃, 400 MHz): δ 0.89 (3H,t, J=7.2 Hz, CH₃), 1.50 (2H, q, J=7.2 Hz, CH₂), 2.48-2.56 (4H, m, CH₂Ar,(CH₂)N), 2.61-2.74 (10H, m, (CH₂)₃N, (CH₂)₂N), 3.20 (4H, t, J=4.8 Hz,(CH₂)₂NPh), 3.60 (2H, bs, NH₂), 6.51-6.54 (2H, m, ArH), 6.57-6.61 (1H,m, ArH), 6.85 (1H, t, J=7.2 Hz, ArH), 6.92 (2H, d, J=8.8 Hz, ArH),7.04-7.08 (1H, m, ArH), 7.24-7.28 (2H, m, ArH). Free base was convertedinto its hydrochloride salt, mp 278-284° C. Elemental analysiscalculated for C₂₃H₃₈N₄Cl₄,0.0475H₂O:C, 53.03; H, 7.54; N, 10.75. FoundC, 53.39; H, 7.96; N, 10.26.

4-Chloro-N-[4-(2-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-propyl-amino}-ethyl)-phenyl]-benzenesulfonamide(30a)

To a stirred solution of 6a (0.04 g, 0.01 mmol) and Et₃N (0.033 g, 0.32mmol) in dry DMF (5 ml) under nitrogen gas was added4-Chloro-benzenesulfonyl chloride and allowed to stir overnight. Waterwas added to the reaction mixture and extracted thrice with diethylether. The combined organic phase was washed with saturated sodiumchloride, dried (Na₂SO₄) and concentrated. The crude product waspurified by chromatography (EtOAc/MeOH=4/1) to produce 30a: 0.042 (75%yield) as a colorless oil. ¹H NMR (CDCl₃, 300 MHz): δ 0.85 (3H, t, J=7.2Hz, CH₃), 1.45 (2H, q, J=7.2 Hz, CH₂), 2.43-2.51 (4H, m, CH₂Ar, (CH₂)N),2.61-2.69 (10H, m, (CH₂)₃N, (CH₂)₂N), 3.19 (4H, t, J=4.8 Hz, (CH₂)₂NPh),6.85 (1H, t, J=7.2 Hz, ArH), 6.91-6.96 (3H, m, ArH), 7.08 (3H, d, J=8.4Hz, ArH), 7.23-7.29 (2H, m, ArH), 7.38 (2H, d, J=8.4 Hz, ArH), 7.62-7.66(2H, d, J=8.7 Hz, ArH). Free base was converted into its hydrochloridesalt, mp 224-226° C. Elemental analysis calculated for C₂₉H₄₀Cl₄N₄O₂S,0.25H₂O: C, 53.17; H, 6.23; N, 8.55. Found C, 53.19; H, 6.43; N, 8.15.

4-Chloro-N-[3-(2-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-propyl-amino}-ethyl)-phenyl]-benzenesulfonamide(30b): (Procedure same as 30a)

29b (0.05 g, 0.136 mmol), Et₃N (0.05 mL, 0.341 mmol) and4-Chloro-benzenesulfonyl chloride (0.043 g, 0.2046 mmol) were reacted(procedure same as for 7a) to afford the title product 30b (0.058 g,78%) as a colorless oil. ¹H NMR (CDCl₃, 300 MHz): δ 0.88 (3H, t, J=7.3Hz, CH₃), 1.45 (2H, q, J=7.1 Hz, CH₂), 1.7 (1H, bs, NH), 2.45-2.55 (4H,m, CH₂Ar, (CH₂)N), 2.62-2.71 (10H, m, (CH₂)₃N, (CH₂)₂N), 3.21 (4H, t,J=4.8 Hz, (CH₂)₂NPh), 6.86 (1H, t, J=7.2, ArH), 6.91-6.95 (3H, m, ArH),7.00 (2H, d, J=7.8, ArH), 7.14-7.19 (3H, m, ArH), 7.39 (2H, d, J=8.7 Hz,ArH), 7.67 (2H, d, J=8.7 Hz, ArH). The free base was converted into itshydrochloride salt, mp 220-224° C. Elemental analysis calculated forC₂₉H₄₀Cl₄N₄O₂S,1.5H₂O: C=51.41; H=6.39; N=8.27. Found C=51.13; H=6.24;N=7.78.

APPENDIX

References

1. Civelli, O., Bunzow, J. R., Grandy, D. K., Molecular Diversity of theDopamine Receptors. ANNU. REV. PHARMACOL. TOXICOL, 32, 281-307, 1993.

2. Seeman, P., Tol Van, H., Dopamine Receptor Pharmacology. TIPS, 15,264-270, 1994.

3. Kebabian, J. W., Calne, D. N., Multiple Receptors for DopamineNATURE, 277, 93-96, 1979.

4. Sokoloff, P., Giros, B., Martres, M.-P., Bouthenet, M.-L., Schwartz,J.-C, Molecular Cloning and Characterization of a Novel DopamineReceptor (D3) as a Target for Neuroleptics. NATURE, 347, 146, 1990.

5. Giros, B., Matres, M. P., Sokoloff, P., Scwartz, J. C. R. ACAD. SCI.[III], 1990, 311, 501.

6. Sokoloff, P. et. al., Dopamine Receptors and TransporterPharmacology, Structure and Function (Niznik, H. B., ed), pp 165-,Marcel Dekker.

7. Livingstone, C. D., Strange, P. G., Naylor, L. H., Molecular Modelingof D2-like Dopamine Receptors. BIOCHEM. J. 287, 277-282, 1992.

8. Seeman, P., SYNAPSE, 1, 133-152, 1987.

9. Jenner, P., Marsden, C. D., Drugs in Central Nervous SystemDisorders, Horwell, D. C., Ed., Marcel Dekker: New York 1985, 149-262.

10. Landwehr, B., Mengod, G., Palacios, J. M., MOL. BRAIN. RES., 18,187-, 1993.

11. Sokoloff, P., Martres, M-P., Giros, B., Bouthenet, M-L., Schwartz,J-C., BIOCHEM. PHARMACOL. 43, 659-, 1992.

12. Schwartz, J-C., Levesque, D., Martes, M-P., Sokoloff, P., CLIN.NEUROPHARMACOL. 16, 295-, 1993.

13. Levant, B., The D3 Dopamine Receptor: Neurobiology and PotentialClinical Relevance, PHARMACOL. REV., 49, 231-252, 1997.

14. Caine, S. B., Koob, G. F., Modulation of Cocaine Self-administrationin the Rat Through D-3 Dopamine Receptors, SCIENCE, 260, 1814-1816,1993.

15. Caine, S. B., Koob, G. F., Pretreatment with the Dopamine Agonist7-oh-dpat Shifts the Cocaine Self-Administration Dose Effect Function tothe Left under Different Schedules in the Rat, BEHAY. PHARMACOL., 6,333-347, 1995.

16. Pilla, M., Perachon, S., Sautel, F., Gamido, F., Mann, A., Wermuth,C., Schwartz, J-C., Everitt, B. J., Sokoloff, P., Selective Inhibitionof Cocaine-seeking Behaviour by a Partial Dopamine D3 Receptor Agonist.NATURE, 400, 371-375, 1999.

17. Canon, J. G., Lee, T., Goldman, H. D., Costall, B., Naylor, R. J.,Cerebral Dopamine Agonist Properties of Some 2-aminotetralin Derivativesafter Peripheral and Intracerebral Administration, J. MED. CHEM., 20,1111-1116, 1977.

18. McDermed, J., McKenzie, G., Phillips, A., Synthesis and Pharmacologyof Some 2-aminotetralins. Dopamine Receptor Agonists, J. MED. CHEM. 18,362-367, 1975.

19. McDermed, J. D., McKenzie, G. M., Freeman, H. S., Synthesis andDopaminergic Activity of (+)-, (+)-, and(−)-2-dipropylamino-5-hydroxy-1,2,3,4-tetrahydronapthalene, J. MED.CHEM. 19, 547-549, 1976.

20. Hacksell, U., Svensson, U., Nilsson, J. L. G., Hjorth, S., Carlsson,A., Wikstrom, H., Lindberg, Sanchez, D., N-Alkylated 2-aminotetralins:Central Dopamine-receptor Stimulating Activity, J. MED. CHEM. 22,1469-1475, 1979.

21. Levesque, D., Diaz, J., Pilon, C., Martres, M.-P., Giros, B., Souil,E., Schott, D., Morgat, J.-L., Schwartz, J.-C., Sokoloff, P.,Identification, Characterization, and Localization of the Dopamine D₃Receptor in Rat Brain Using7-[³H]hydroxy-N,N-di-n-propyl-2-aminotetralin. PROC. NATL. ACAD. SCI.U.S.A., 89, 8155-8159, 1992.

22. Alexander van Vliet, L., Tepper, P. G., Dijkstra, D., Damsma, G.,Wikstrom, H., Pugsly, T. A., Akunne, H. C., Heffner, T. G., Glase, S.A., Wise, L. D., Affinity for Dopamine D₂, D₃ and D₄ Receptors of2-aminotetralins. Relevance of D₂ Agonist Binding for Determination ofReceptor Subtype Selectivity, J. MED. CHEM. 39, 4233-4237, 1996.

23. John Murray, P., Harrison, L. A., Johnson, M. R., Robertson, G. M.,Scopes, D. I., Bull, D. R., Graham, E. A., Hayes, A. G., Kilpatrick, G.J., Dass, I. D., Large, C., Sheehan, M. J., Stubbs, C. M., Turpin, M.P., A Novel Series of Arylpiperazines with High Affinity and Selectivityfor the Dopamine D₃ Receptor, BIOORG. MED. CHEM. LETT., 5, 219-222,1995.

24. Teran, C., Santana, L., Uriarte, E., Fall, Y., Unelius, L., Tolf,B-R, Phenylpiperazine Derivatives with Strong Affinity for 5HT1a, D2Aand D3 Receptors, BIOORG. MED. CHEM. LETT., 8, 3567-3570, 1998.

25. Boyfield, I., Coldwell, M. C., Hadley, M. S., Johnson, C. N., Riley,G. J., Scott, E. E., Stacey, R., Stemp, G., Thewlis, K. M., A NovelSeries of 2-aminotetralins with High Affinity and Selectivity for theDopamine D₃ Receptor. BIOORG. MED. CHEM. LETT., 7, 1995-1998, 1997.

26. Yuan, J., Chen, X., Brodbeck, R., Primus, R., Braun, J., Wasley, J.F., Thurkauf, A., NGB 2904 and NGB 2849: Two Highly Selective DopamineD₃ Receptor Antagonist. BIOORG. MED. CHEM. LETT., 8, 2715-2718, 1998.

27. Homan, E. J., Coping a, S., Elfstrom, L., Veen, T., Hallema, J-P.,Mohell, N., Unelius, L., Johansson, R., Wikstrom, H. V., Grol, C. J.,2-aminotetralin-derived Substituted Benzamide with Mixed Dopamine D₂,D₃, and Serotonin 5-HT1A Receptor Binding Properties: A Novel Class ofPotential Atypical Antipsychotic Agents, BIOORG. MED. CHEM., 6,2111-2126, 1998.

28. Avenell, K. Y., Boyfield, I., Hadley, M. S., Johnson, C. N., Nash,D. J., Riley, G. J., Stemp, G., Heterocyclic Analogues of2-aminotetralins with High Affinity and Selectivity for the Dopamine D₃Receptor, BIOORG. MED. CHEM. LETT. 9, 2715-2720, 1999.

29. Pugsley, T. A., Davis, H. C. Akunne, H. C., Mackenzie, R. G., Shih,Y. H., Damsma, G., Wikstrom, H., Whetzel, S. Z., Georgic, L. M., Cooke,L. W., Demattos, S. B., Corbin, A. E. Glase, S. A., Wise, L. D.,Dijkstra, D., Heffner, T. G., J. PHARMACOL. EXP. THER., 275, 1355-1366,1995.

30. Pilon, C., Levesque, D., Dimitriadou, V., Griffon, N., Martres, M.P., Schwartz, J. C., and Sokoloff, P., EUR. J. PHARMACOL., 268: 129-139,1994.

31. Millan, M. J. et al., J. PHARMACOL. EXP. THER., 286, 1341-1355,1998.

32. Ravina, E. et al., J. MED. CHEM., 43, 4678-4693, 2000.

33. Watts, V. J., Lawler, C. P., Knoerzer, T., Mayleben, M. A., Neve, K.A., Nichols, D. E., Mailman, R. B., EUR. J. PHARMACOL., 239, 271-273,1993.

34. Dutta, A. K., Fei, X.-S., Reith, M. E. A., BIORG. MED. CHEM. LETT.,12:4:619-6, 2002.

35. Kula, N. S. et al., CELL. MOL. NEUROBIOL., 14, 185-191, 1994.

1. A compound having the structure (I)

wherein A is an optionally heterocyclic aromatic ring system containingfrom 1 to 4 aromatic or heteroaromatic rings, optionally fused;

comprises an aromatic ring system wherein X and Y are moieties whichcomplete a 5 or 6 membered aromatic ring optionally containing N, O, S,or Se heteroatoms; R² is a C₁₋₁₀ hydrocarbon group substituent or two R²together may form a fused ring system, said hydrocarbon group and saidfused ring system optionally containing one or more O, N, S, or Seheteroatoms, or R² is a hydroxyl or amino group, o is an integer from 0to 4, the upper limit of o bounded by the number of availablesubstitutent sites on said optionally heterocyclic 5 or 6 memberedaromatic ring structure; n is 0 or 2; R¹ is an organyl group selectedfrom the group consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₄₋₈ cycloalkyl, C₄₋₈ cycloalkenyl, C₆₋₁₀ aryl, each of the foregoingalkyl, alkenyl, alkynyl, cycloalkyl, etc. groups optionally halosubstituted and/or substituted by —CN, C₁₋₄ lower alkoxy, C₁₋₄ acyloxy,C₁₋₄ acyl, or —C(O)—R⁴; —R⁵—NH—SO₂—NR⁴, where R⁵ is C₁₋₈ alkylene and ris 2 or 3, with the proviso that when r is 3, the nitrogen of the NR⁴,group will bear a positive formal charge; —R⁵—NH—C(O)—R⁴; —R5—NR_(r)⁴—R5—Ar where Ar is an aryl ring system, optionally including one ormore O, N, S, or Se heteroatoms and wherein R¹, together with (CH₂)_(p)may form an alicyclic sic membered ring, and wherein R¹, together withthe six membered alicyclic ring of structure (I) may form a fused sixmembered alicyclic ring; p is 1 to 4; wherein one (CH₂)_(n) group may bereplaced by O, or S, or Se; or a pharmaceutically acceptable salt,ester, carbamate, or amide thereof.
 2. The compound of claim 1 wherein:R² is selected from the group consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₄₋₈ cycloalkyl, C₄₋₈ cycloalkenyl; C₆₋₁₀ aryl, —NR⁴ _(q)where R⁴ individually are H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₄₋₈ cycloalkyl,C₄₋₈ cycloalkenyl, C₆₋₁₀ aryl and q is 3 or 4, with the proviso thatwhen q is 4, the group bears a positive formal charge; —NR⁴—C(O)—R⁴,—NR⁴—C(O)—NR⁴ ₂ wherein the above hydrocarbon groups may optionally besubstituted with —CN, C₁₋₄ lower alkyl, —OR⁴, —OH, and halo; and A is anoptionally heterocyclic aromatic ring system containing 1 to 4optionally fused aromatic five or six membered rings, one or more ringsoptionally substituted by one or more C₁₋₄ alkyl, C₂₋₄ alkenyl, C₅₋₇cycloalkyl, C₅₋₇ cycloalkenyl, halo, C₁₋₄ aldehydo, or —NR_(q) ⁴ groups.3. The compound of claim 1 wherein A is selected form the groupconsisting of phenyl, 2-methoxyphenyl, 2,3-dichlorophenyl,4-(methylsulfonamino)phenyl, and biphenyl.
 4. A compound of claim 1,selected from the group consisting of:

and pharmaceutically acceptable salts, esters, carbamates, and amidesthereof, wherein each Z independently is O, N, S, Se, or a CH or CH₂.